ORCID Profile
0000-0003-4300-0521
Current Organisation
UNSW Sydney
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Publisher: SAGE Publications
Date: 09-2021
DOI: 10.1177/25161032211036162
Abstract: Asylum-seeking children presenting in the shutdown state have been the subject of much discussion and controversy—on both government and medical system levels—in Australia and in Sweden. In this article, we conceptualize the shutdown state as an evolutionary response to extreme threat. We adopt a neuroscience approach to present five plausible models for explaining this shutdown state, their strengths and shortcomings, and the overlaps between them. Model 1—the sustained autonomic arousal model—draws on polyvagal theory. Model 2—the innate-defence model—draws on research pertaining to animal and human innate defence responses. Model 3—the catatonia model—draws on clinical and research data with patients presenting with catatonia. Model 4—the hypometabolic model—draws on an emerging body of work pertaining to hypometabolic states in animals and humans. Model 5—the defence cascade model of dissociation—draws on clinical research pertaining to human trauma states that present as dissociation. At present, each of the models provides a plausible pathophysiological explanation—or a component of a potential pathophysiological explanation—and none of them, for the moment, has enough evidence to be either accepted or disregarded. We hope that our discussion of the models advances scientific discussion and opens up possibilities for effective treatment.
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0304-3940(97)13395-X
Abstract: We investigated the changes in Fos-like immunoreactivity in the locus coeruleus (LC) after classical conditioning of the rabbit's nictitating membrane. Specifically, we compared unpaired versus paired presentations of a tone conditioned stimulus (CS) and a tactile unconditioned stimulus (US near the eye). After two training sessions, only paired presentations resulted in acquisition of a conditioned response. This was associated with comparatively less LC Fos expression than with unpaired presentations. Similar observations have been reported for the ventrolateral medulla which is a major source of afferents to LC. The present results are consistent with a role of LC in attention and learning: activity increases as the animal attends to the CS and US. When the relationship between CS and US has been established, LC activity decreases.
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.AUTNEU.2004.08.014
Abstract: A spinal cord transection at the fourth thoracic level (T4) results in paraplegia. It also removes supraspinal control of sympathetic outflow to most viscera and their blood vessels but spares the heart. We studied the effects of such a transection on the expression of the conditioned fear response to context, which includes freezing, 22 kHz ultrasonic vocalisations, a marked pressor response and a slowly rising tachycardia. Rats implanted with radiotelemetric probes were fear conditioned, tested, then transected at T4 and finally re-tested 4 weeks after transection. Baseline blood pressure in transected animals was the same as in intact animals but baseline heart rate was 127 bpm higher. There were clear signs of fear in the transected animals: although freezing occurred in the upper part of the body only, there was a 3 fold increase in the number of ultrasonic vocalisations, most probably due to paralysis of abdominal muscles that made expirations shorter and therefore more frequent. The pressor response of fear was initially the same as in intact animals but controls revealed that this was due to handling during transfer to the aversive context. The rest of the pressor response was markedly reduced (70%) confirming that it depends in large part on a sympathetically mediated increase in vascular resistance in the lower part of the body. The cardiac response was characterized by an initial bradycardia followed by a marked tachycardia, which is consistent with a baroreceptor-mediated reflex response to the altered pressor changes. Finally, none of these changes was observed when the same experiment was repeated in sham transected animals. Thus, the pressor response of fear is in large part mediated by the thoracic cord below T4 and the baroreflex is not inhibited but maintained during conditioned fear.
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S0306-4522(99)00488-1
Abstract: We showed recently that conditioned fear to context induces Fos expression in the ventrolateral periaqueductal gray [Neuroscience (1997) 78, 165-177]. Neurons in this region are thought to play an important role in the expression of freezing during conditioned fear. To test the possibility that this activation comes directly from the amygdala, we looked at changes in Fos expression after a unilateral blockade of the ventral amygdalofugal pathway with lidocaine. The pathway contains fibres originating from the central nucleus of the amygdala that project directly and mainly ipsilaterally to the ventrolateral periaqueductal gray. Conditioned fear was evoked by re-exposing rats to the same box in which they had previously received electric footshocks. The test re-exposure was preceded by a unilateral microinjection of lidocaine (2%, 0.5-1 microl n = 20) or saline (n = 14). Lidocaine was also tested in non-conditioned animals (n = 13). The results show that, when lidocaine was microinjected in the medial part of the central nucleus of the amygdala or along the ventral amygdalofugal pathway of conditioned rats, fear-induced Fos expression in the ventrolateral periaqueductal gray was reduced on the side ipsilateral to the injection (up to 37% reduction in comparison to the contralateral side). Ipsilateral reductions were also observed with saline, but they were weaker (maximum of 27% reduction). Fos expression remained low on both sides in the non-fear-conditioned animals injected with lidocaine. Finally, although freezing was only partly reduced in the conditioned animals unilaterally injected with lidocaine, it was significantly correlated to the ipsilateral reduction in Fos expression. This study provides direct evidence that the projection from the central nucleus of the amygdala to the ventrolateral periaqueductal gray is activated during fear and that it contributes to the Fos response of the ventrolateral periaqueductal gray.
Publisher: Elsevier BV
Date: 08-1985
Publisher: Elsevier BV
Date: 02-1991
DOI: 10.1016/0006-8993(91)91020-2
Abstract: Microinjection of the excitatory amino acid D,L-homocysteic acid (40 nmol, in 200 nl) made into the ventrolateral part of the caudal half (A2.5-P1.5) of the midbrain periaqueductal gray (PAG) of the decerebrate cat evoked a hypotensive reaction associated with a slowing of the heart and a decrease in either external iliac or renal vascular resistance. The decrease in iliac vascular resistance was elicited from the pretentorial portion (A2.5-A0.6) of the PAG hypotensive area, whereas the decrease in renal vascular resistance was elicited from the subtentorial portion (A0.6-P1.5). Anatomical experiments using the method of retrograde transport of rhodamine-labelled microspheres or wheat germ agglutinin-horseradish peroxidase demonstrated topographically organized projections from the ventrolateral PAG to the subretrofacial (SRF) pressor nucleus in the rostral ventrolateral medulla. The pretentorial part of the ventrolateral PAG projected mainly to the caudal part of the SRF nucleus, which preferentially controls iliac vascular resistance. The subtentorial part of the ventrolateral PAG projected mainly to the rostral part of the SRF nucleus, which preferentially controls renal vascular resistance. Taken together, these findings suggest: (i) that neurons within the ventrolateral PAG are viscerotopically organized and (ii) that their hypotensive function may be mediated by an inhibition of SRF pressor neurons. The results are discussed in relation to the recently described PAG hypertensive area which also is viscerotopically organized and projects to the SRF nucleus.
Publisher: Wiley
Date: 24-11-2006
Publisher: Elsevier BV
Date: 08-1985
Publisher: Wiley
Date: 04-2011
Publisher: Elsevier BV
Date: 02-2001
DOI: 10.1016/S0306-4522(00)00513-3
Abstract: Activation of the ventrolateral periaqueductal gray produces immobility and antinociception. It has been argued that these behaviors are part of either a defensive fear response to threat or a recuperative quiescence response to deep tissue injury. Data collected in anesthetized animals showing that activation of the ventrolateral periaqueductal gray has a hypotensive effect supports the quiescence hypothesis. Our objective was to determine whether activation of the ventrolateral periaqueductal gray in awake, freely moving rats results in a decrease in blood pressure as it does in anesthetized animals. Changes in blood pressure produced by microinjection of the neuroexcitant D,L-homocysteic acid were measured using radio telemetry while rats were awake and while anesthetized with pentobarbital. Consistent with earlier reports, microinjection of D,L-homocysteic acid into the ventrolateral periaqueductal gray caused a decrease in blood pressure in anesthetized rats. In contrast, microinjection at the same ventrolateral periaqueductal gray sites while rats were awake had no effect on blood pressure, even though the animals became immobile and heart rate decreased. Thus, the immobility evoked from ventrolateral periaqueductal gray is not associated with a fall in mean arterial pressure. Two conclusions can be drawn from these data. (1) Caution must be used in generalizing from data collected in anesthetized animals. (2) The ventrolateral periaqueductal gray is as likely to contribute to defensive fear as to recuperative quiescence.
Publisher: Elsevier BV
Date: 04-1989
DOI: 10.1016/0006-8993(89)90169-8
Abstract: Microinjections of the excitant amino acid D,L-homocysteic acid (DLH) made in a restricted part of the subtentorial (P0.2-P0.9) midbrain periaqueductal grey (PAG) of the unanesthetized decerebrate cat evoked a distinctive pattern of coordinated somatic and autonomic changes which was characterized by strenuous hindlimb movement and a concomitant vasodilation in the hindlimb vascular bed. The vasodilation was not secondary to movement as it could still be evoked in the paralyzed preparation. The autonomic changes also included pupillary dilation, increases in arterial pressure and heart rate, and vasoconstriction in renal and mesenteric vascular beds. This evoked response is quite different from that elicited by DLH microinjections made in a restricted part of the pretentorial PAG of the unanesthetized cat (Carrive et al., Neurosci. Lett., 81 (1987) 273-278). This latter response is characterized by a threat display which includes strong facial and vocal changes, but no strenuous hindlimb movement, and skeletal muscle vasoconstriction. The present results together with our previous research suggest that two distinct sets of neurons located in different midbrain PAG regions mediate coordinated patterns of somatic and autonomic change characteristics of different aspects of defensive behavior.
Publisher: Elsevier BV
Date: 10-1987
DOI: 10.1016/0304-3940(87)90395-8
Abstract: Microinjections of the excitant amino acid D,L-homocysteic acid (DLH) into a restricted part of the midbrain periaqueductal grey (PAG) of unanaesthetized decerebrate cats evoked a distinctive pattern of facio-vocal and cardiovascular changes characteristic of a defence reaction, including pupillary dilatation, howling vocalization, an increase in arterial pressure and heart rate, and skeletal muscle vasoconstriction. These facio-vocal and cardiovascular responses always occurred together, and thus may arise from excitation of a common population of neurones. DLH injections within a greater extent of the PAG elicited other facio-vocal changes characteristic of defence, such as hissing or growling, but these were not accompanied by significant cardiovascular changes.
Publisher: Elsevier BV
Date: 06-1988
DOI: 10.1016/0091-3057(88)90464-9
Abstract: Behavioral effects of unilateral microinjections into periventricular structures of bicuculline, a classic GABA-A antagonist, and semicarbazide, a glutamic acid decarboxylase blocker, were studied in detelencephalated rats. These drugs produced a behavioral activation together with jumps. However, the characteristics of this behavioral activation differed as the injections were made in dorsal periaqueductal gray matter or medial hypothalamus. These data show close similarities to those observed with intact animals suggesting that GABA-A receptors are involved in the neural control of expression of flight behavior and functions in an intact manner and possibly independent of influences from forebrain structures. At variance with intact animals, these drugs produced contralateral turning behavior when locally injected into MH, pointing to some kind of inhibitory control exerted by telencephalic structures on the expression of circling behavior from diencephalic regions.
Publisher: American Physiological Society
Date: 02-2008
DOI: 10.1152/AJPHEART.01002.2007
Abstract: Autonomic dysreflexia (AD) is a debilitating disorder producing episodes of extreme hypertension in patients with high-level spinal cord injury (SCI). Factors leading to AD include loss of vasomotor baroreflex control to regions below injury level, changes in spinal circuitry, and peripheral changes. The present study tested for peripheral changes below and above injury level 6 wk after a transection at the fourth thoracic spinal level. Changes in vascular conductance were recorded in the femoral, renal, brachial, and carotid arteries in response to intravenous injections of two α-adrenergic agonists, phenylephrine (PE 0.03–100 μg/kg) and methoxamine (Meth 1–300 μg/kg). Unlike PE, Meth is not subject to neuronal reuptake. Ganglionic blockade (0.6 mg/kg chlorisondamine) was used to eliminate the central component of the cardiovascular response. After ganglionic blockade, SCI animals exhibited prolonged vasoconstriction in response to PE in all blood vessels measured compared with those in intact animals (all, P 0.035). However, the PE dose-response curves obtained after ganglionic blockade revealed no significant difference in the potency between the two groups (all, P 0.06), indicating that the prolonged vasoconstriction was not due to supersensitivity to PE. In contrast to PE, vascular responses to Meth did not vary between intact and SCI groups (all P 0.108). These results show the development of a widespread peripheral change producing prolonged vasoconstriction in response to PE, but not Meth, possibly due to reduced neuronal reuptake of PE after SCI. This is the first study to report such a change in blood vessels not only below but also above injury level. Interventions to correct this reduced reuptake may help limit the development of AD.
Publisher: Elsevier
Date: 2009
Publisher: Wiley
Date: 12-2006
DOI: 10.1111/J.1440-1681.2006.04519.X
Abstract: 1. The present study investigates the contribution of the sympathetic and vagal parasympathetic systems to the tachycardic response of long-lasting (40 min) conditioned fear responses to context. 2. The conditioned fear response evoked by re-exposure to a footshock chamber was tested 10 min after intravenous injection of the beta-adrenoceptor antagonist propranolol (2 mg/kg) or the muscarinic antagonist atropine methyl nitrate (2 mg/kg) in rats implanted with radiotelemetric probes. 3. Compared with saline controls, the drugs did not change the behavioural component of the response (freezing, 22 kHz ultrasonic vocalizations) or its pressor component (+28 mmHg). 4. Propranolol abolished the tachycardic response of fear, whereas atropine more than doubled it (from +75 to +175 b.p.m. above resting baseline). 5. The results demonstrate that both sympathetic and vagal parasympathetic outflows to the heart are strongly activated during conditioned fear. The vagal activation may act to hold back cardiac acceleration while the animal waits for the aversive stimulus to come.
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.NEUROSCIENCE.2007.11.027
Abstract: Ionotropic purinergic receptors (P2XR) are ATP-gated cationic channels composed of seven known subunits (P2X(1-7)R) and involved in different functions in neural tissue. Although their presence has been demonstrated in the brain, few studies have investigated their expression pattern. In particular, ionotropic purinergic receptor subunit type 1 (P2X(1)R) has been observed in the cerebellum and in brainstem nuclei. The present study investigates the P2X(1)R expression pattern in the rat forebrain using immunohistochemistry. The specificity of the immunolabeling has been verified by Western blotting and in situ hybridization methods. P2X(1)R immunoreactivity was specifically localized in neurons, dendrites and axons throughout the forebrain. Characteristic differences in the distribution of P2X(1)R were observed in different cortical areas. In prefrontal, cingulate and perirhinal cortices, very intense labeling was present in neuronal bodies. In frontal, parietal, temporal and occipital cortices, immunostaining was lighter and mainly found in dendrites and axons. The hippoc al formation was intensely labeled. Labeling was present almost exclusively in dendrites and axons and never in neuronal bodies. The diencephalon was devoid of P2X(1)R positive neurons or fibers except for the medial habenular nucleus, which showed very intense P2X(1)R immunostaining. Furthermore, two subcortical regions, namely, the nucleus centralis of the amygdala and the bed nucleus of the stria terminalis, showed intense P2X(1)R neuronal labeling. Present data indicate that P2X(1)R are prevalent in forebrain areas involved in the integration of cognitive, limbic and autonomic functions.
Publisher: Elsevier BV
Date: 08-2009
Publisher: American Psychological Association (APA)
Date: 12-2017
DOI: 10.1037/BNE0000217
Abstract: The midbrain periaqueductal gray (PAG) coordinates the expression and topography of defensive behaviors to threat and also plays an important role in Pavlovian fear learning itself. Whereas the role of PAG in the expression of defensive behavior is well understood, the relationship between the activity of PAG neurons and fear learning, the exact timing of PAG contributions to learning during the conditioning trial, and the contributions of different PAG columns to fear learning are poorly understood. We assessed the effects of optogenetic inhibition of lateral (LPAG) and ventrolateral PAG (VLPAG) neurons on fear learning. Using adenoassociated viral vectors expressing halorhodopsin, we show that brief optogenetic inhibition of LPAG or VLPAG during delivery of the shock unconditioned stimulus (US) augments acquisition of contextual or cued fear conditioning, and we also show that this inhibition augments postencounter defensive responses to a nonnoxious threat. Taken together, these results show that LPAG and VLPAG serve a key role in the regulation of Pavlovian fear learning at the time of US delivery. These findings provide strong support for existing models that state that LPAG and VLPAG contribute to a fear prediction error signal determining variations in the effectiveness of the aversive US in supporting learning. (PsycINFO Database Record
Publisher: Elsevier BV
Date: 06-1990
DOI: 10.1016/0006-8993(90)91692-A
Abstract: Unilateral microinjections of the excitatory amino acid, D,L-homocysteic acid (DLH) made in the lateral and ventrolateral parts of the subtentorial (A 1.0-P 1.5) midbrain periaqueductal gray (PAG) of the freely moving cat evoked two distinct patterns of coordinated somatic changes. When DLH injection (80 nmol) was made within the lateral part of the subtentorial PAG it evoked a flight reaction, characterized by strong locomotion (running) and multiple jumps. This flight reaction was quite distinct from the defensive threat display previously described following DLH microinjection in the lateral part of the pretentorial PAG. When DLH injection (80 nmol) was made in the subtentorial PAG region, ventrolateral to the aqueduct, it elicited a cessation of both spontaneous locomotion and general movements (e.g. licking, scratching, grooming, head and limb movements), a reaction termed immobility. The subtentorial PAG regions from which flight and immobility were evoked are seemingly identical to the lateral and ventrolateral subtentorial PAG regions in which hypertensive and hypotensive reactions have been evoked previously by DLH microinjection. The present results together with our previous studies suggest that: (1) the lateral PAG of the cat contains at least two, topographically separable neuronal pools, which mediate different types of defense reactions (i.e. threat display--lateral part of the pretentorial PAG flight reaction--lateral part of the subtentorial PAG) and (2) excitation of neurons in the ventrolateral PAG alters autonomic and somatic functions, but in a direction opposite to that of lateral PAG neurons, namely decreased somatomotor activity and hypotension.
Publisher: SAGE Publications
Date: 28-09-2017
Abstract: Psychogenic non-epileptic seizures (PNES) – time-limited disturbances of consciousness and motor-sensory control, not accompanied by ictal activity on electroencephalogram (EEG) – are best conceptualized as atypical neurophysiological responses to emotional distress, physiological stressors and danger. Patients and families find the diagnosis of PNES difficult to understand the transition from neurology (where the diagnosis is made) to mental health services (to which patients are referred for treatment) can be a bumpy one. This study reports how diagnostic formulations constructed for 60 consecutive children and adolescents with PNES were used to inform both the explanations about PNES that were given to them and their families and the clinical interventions that were used to help patients gain control over PNES. Families were able to accept the diagnosis of PNES and engage in treatment when it was explained how emotional distress, illness and states of high arousal could activate atypical defence responses in the body and brain – with PNES being an unwanted by-product of this process. Patients and their families made good use of therapeutic interventions. A total of 75% of children/adolescents (45/60) regained normal function and attained full-time return to school. Global Assessment of Functioning scores increased from 41 to 67 ( t(54) = 10.09 p .001). Outcomes were less favourable in children/adolescents who presented with chronic PNES and in those with a chronic, comorbid mental health disorder that failed to resolve with treatment. The study highlights that prompt diagnosis, followed by prompt multidisciplinary assessment, engagement, and treatment, achieves improved outcomes in children/adolescents with PNES.
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.NLM.2017.07.006
Abstract: The midbrain periaqueductal gray (PAG) has been implicated in the generation and transmission of a prediction error signal that instructs amygdala-based fear and extinction learning. However, the PAG also plays a key role in the expression of conditioned fear responses. The evidence for a role of the PAG in fear learning and extinction learning has been obtained almost exclusively using PAG-dependent fear responses. It is less clear whether the PAG regulates fear learning when other measures of learned fear are used. Here we combined a chemogenetic approach, permitting excitation or inhibition of neurons in the ventrolateral PAG (VLPAG), with conditioned suppression as the measure of learned fear to assess the role of VLPAG in the acquisition and extinction of fear learning. We show that chemogenetic excitation of VLPAG (with some encroachment on lateral PAG [LPAG]) impairs acquisition of fear and, conversely, chemogenetic inhibition impairs extinction of fear. These effects on fear and extinction learning were specific to the combination of DREADD expression and injection of CNO because they were observed relative to both eYFP controls injected with CNO as well as DREADD expressing controls injected with vehicle. Taken together, these results show that activity of L/VLPAG neurons regulates both the acquisition and extinction of Pavlovian fear learning.
Publisher: Wiley
Date: 2006
DOI: 10.1002/CNE.21013
Abstract: Neurophysiologic data suggest that orexin neurons are directly excited by ATP through purinergic receptors (P2XR). Anatomical studies, though reporting P2XR in the hypothalamus, did not describe it in the perifornical hypothalamic area, where orexinergic neurons are located. Here we report the presence of the P2X(2)R subunit in the rat perifornical hypothalamus and demonstrate that hypothalamic orexin neurons express the P2X(2)R. Double immunohistochemistry showed that virtually all orexin-immunoreactive neurons are also P2X(2)R immunoreactive, whereas 80% of P2X(2)R-immunoreactive neurons are also orexin positive. Triple-labeling experiments, combining fluorescence in situ hybridization for P2X(2)R mRNA and P2X(2)R/orexin double immunofluorescence, confirmed these findings. In addition, in situ hybridization demonstrated that P2X(2)R mRNA is localized in cellular processes of orexinergic neurons. The present data support neurophysiologic findings on ATP modulation of orexinergic function and provide direct evidence that the entire population of orexin neurons expresses a P2XR subtype, namely, P2X(2)R. Thus, purinergic transmission might intervene in modulating key functions known to be controlled by the orexinergic system, such as feeding behavior and arousal.
Publisher: Frontiers Media SA
Date: 2013
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.NLM.2022.107657
Abstract: Instrumental actions are initially goal-directed but with repeated performance can become habitual. Habitual actions are adaptive, learned behaviours that are automated in order to reduce cognitive load and to allow for efficient interaction with the environment. Goal-directed and habitual actions are mediated by distinct neurocircuits which centre on the dorsal striatum and involve different cortical and limbic inputs. The lateral hypothalamus (LH) has yet to be considered in this neurocircuitry despite its anatomical connections with these neurocircuits and its established role in motivated behaviour. The aim of the current study was to determine whether the LH has a role in the development of habitual actions in rats by knocking down protein expression in the LH with short hairpin RNAs (shRNA). Two shRNAs were utilised, both of which were shown to reduce the expression of two neuropeptides within the LH, orexin and melanin-concentrating hormone, compared to a saline-vehicle control. This was unexpected given that one shRNA was a control vector (i.e, scrambled sequence), and the other shRNA was supposed to selectively target orexin's precursor protein. Given this lack of specificity and that shRNA's are known to be neurotoxic, the current study examined the impact of non-selective dysfunction of the LH on habitual actions. Adult male Long-Evans rats were trained to press a lever for a food outcome and were tested for goal directed and habitual behaviour following devaluation of the food. The shRNA groups displayed goal-directed actions following moderate instrumental training, but did not develop habitual actions following extended training. That is, control rats developed the expected habitual behaviour where lever-response rates were insensitive to outcome value when tested, whilst the shRNA groups reduced rates of responding on the lever under devalued conditioned and hence remained goal-directed. This failure to demonstrate habitual actions was unlikely to be secondary to changes in motivation or arousal as the shRNA groups did not show altered food consumption, body weight, lever response rates, or motor performance on a rota rod or tapered balance beam. However, locomotor activity was reduced in an open field test, consistent with the proposed role of the LH in spontaneous locomotor activity. Therefore, this study implicates the LH in habitual learning, and adds to the emerging evidence that the LH has a role in associative learning processes. This finding has implications for human conditions where there is dysfunction or neurodegeneration in the LH, as well as altered habitual actions, such as in Parkinson's disease and drug addiction.
Publisher: Springer International Publishing
Date: 2017
DOI: 10.1007/7854_2016_46
Abstract: Orexin makes an important contribution to the regulation of cardiorespiratory function. When injected centrally under anesthesia, orexin increases blood pressure, heart rate, sympathetic nerve activity, and the litude and frequency of respiration. This is consistent with the location of orexin neurons in the hypothalamus and the distribution of orexin terminals at all levels of the central autonomic and respiratory network. These cardiorespiratory responses are components of arousal and are necessary to allow the expression of motivated behaviors. Thus, orexin contributes to the cardiorespiratory response to acute stressors, especially those of a psychogenic nature. Consequently, upregulation of orexin signaling, whether it is spontaneous or environmentally induced, can increase blood pressure and lead to hypertension, as is the case for the spontaneously hypertensive rat and the hypertensive BPH/2J Schlager mouse. Blockade of orexin receptors will reduce blood pressure in these animals, which could be a new pharmacological approach for the treatment of some forms of hypertension. Orexin can also magnify the respiratory reflex to hypercapnia in order to maintain respiratory homeostasis, and this may be in part why it is upregulated during obstructive sleep apnea. In this pathological condition, blockade of orexin receptors would make the apnea worse. To summarize, orexin is an important modulator of cardiorespiratory function. Acting on orexin signaling may help in the treatment of some cardiovascular and respiratory disorders.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2015
Publisher: Elsevier BV
Date: 11-1986
DOI: 10.1016/0166-4328(86)90039-2
Abstract: This paper reviews results obtained in experiments concerning the neurochemical characteristics of the substrate involved in the control of flight reactions and the induction of aversive effects in the rat. These experiments investigated the behavioural effects produced by microinjecting into the periaqueductal grey matter (PAG) or the medial hypothalamus (MH) compounds known to interfere with the functioning of some neurotransmitter systems known to exist in these structures. The data obtained show that: the activity of the substrate involved in the production of flight reactions is tonically inhibited by the release of GABA (gamma-aminobutyric acid) the behavioural reactions produced by microinjecting GABA antagonists can be clearly distinguished, depending on whether such drugs were injected into the PAG or the MH, despite the fact that jumps were produced from either level behavioural effects, comparable to some extent to those produced by microinjections of GABA antagonists, can be obtained by injecting drugs which act on non-GABAergic neurochemical substrates, namely opioidergic or cholinergic systems and behavioural effects, comparable to those produced by injecting GABA antagonists into the PAG, can be obtained by injecting such drugs into various sites located in other parts of the tectum such as the inferior colliculus or adjacent structures.
Publisher: Elsevier BV
Date: 07-1989
DOI: 10.1016/0006-8993(89)91176-1
Abstract: It is well established that a group of bulbospinal neurons within the rostral ventrolateral medulla plays a crucial role in the tonic and phasic control of arterial pressure. In the cat, these neurons are confined to a discrete region which has been termed the subretrofacial (SRF) nucleus. Recent evidence suggests that this nucleus is viscerotopically organized with respect to its control over different vascular beds. These observations raise the question as to whether functionally different subgroups of SRF pressor neurons receive inputs from supramedullary cell groups that also exert a specific control over particular vascular beds. To answer this question retrogradely transported tracers (i.e. rhodamine or fluorescein-labelled microspheres, wheat germ agglutinin-horseradish peroxidase) were injected into physiologically identified sites within the rostral or caudal parts of the SRF nucleus of the cat. Separate groups of neurons in the midbrain periaqueductal gray region (PAG) were found to project specifically to subgroups of cells within the rostral and caudal parts of the SRF nucleus. These findings, together with the results of recent functional studies of the PAG suggest that these distinct projections from the PAG to the SRF nucleus are involved in the expression of different patterns of emotionally coupled cardiovascular responses.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-1997
DOI: 10.1016/S0304-3959(97)03325-8
Abstract: This study compares the effects of two non-steroidal anti-inflammatory drugs, Bufferin A (BA) and L-5409709 (L-54), on nociceptive behaviour and spinal Fos expression induced by subcutaneous formalin in the rat. BA contains aspirin. L-54 contains ibuprofen, caffeine and paracetamol. Doses based on the human posology were administered orally 30 or 40 min before subcutaneous intraplantar injection of formalin (1.5%, 50 microl) in the right hindpaw. Low doses (BA, 24 mg/kg L-54, 21.5 mg/kg) did not significantly affect the behavioural pain response. High doses (BA, 480 mg/kg L-54, 430 mg/kg) reduced the late phase of the response by 42% and 62% respectively, but did not affect the early phase of the response. No sedative side-effects were observed. The two drugs had different effects on the number of spinal Fos-like immunoreactive neurones 2 h after the formalin injection. Fos expression was reduced after BA treatment, and this reduction was correlated to and matched the reduction of the pain response. In contrast, Fos expression after L-54 treatment was not reduced and was not correlated to the reduction in the pain response. The Fos results reveal clear differences in the way that BA (aspirin) and L-54 (ibuprofen + caffeine + paracetamol) affected transmission of the noxious signal. They suggest that BA did not act beyond the spinal cord and that L-54 had more central sites of action than BA.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
DOI: 10.1016/J.PAIN.2010.12.019
Abstract: An increased tail-flick latency to noxious heat during or after stress in the rodent is usually interpreted as a stress-induced reduction in pain sensitivity and often described as a form of stress-induced "analgesia." However, this measure is an indirect and flawed measure of the change in nociceptive threshold to noxious heat. A major confound of the latency measure is the initial temperature of the tail, which can drop down to room temperature during stress, the consequence of a marked sympathetically mediated vasoconstriction in the skin of the extremities. We addressed this issue with tail-flick tests during contextual fear using infrared thermography to monitor temperature changes and a CO2 laser to deliver the heat stimulus. The experiment revealed a 4.2°C increase of the nociceptive threshold, confirming a true antinociceptive effect. However, its contribution to the increased withdrawal latency was less than two-thirds (63.2%). Nearly one-third (32.2%) was due to the drop in tail temperature (4.4°C), which also slowed conduction along sensory fibers (2.2%, included in the 32.2%). The remaining 4.6% was due to an increase in decisional/motor latency. This new unbiased method establishes beyond doubt that a conditioned stress response is associated with true antinociception to noxious heat. It also confirms that stress-induced changes in skin temperature can be a major confound in tail-flick tests. The present study shows, for the first time, the exact contribution of these two components of the tail-flick latency for a stress response. Less than two-thirds of the increase in tail-flick latency to noxious heat, evoked by conditioned fear, reflects true antinociception. The remaining is due to skin vasoconstriction.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.EJPHAR.2019.172595
Abstract: After social stress, rats become vulnerable to depression, and this state is characterized by persistent low blood levels of brain-derived neurotrophic factor (BDNF). The aim of this study was to determine whether low BDNF levels are associated with long term autonomic changes. Defeated animals were subjected to four daily episodes of social defeats. Twenty five days later, defeated rats with low BDNF levels (Dlow) still displayed elevated sympathetic tone (as indicated by an elevated low frequency to high frequency ratio (LF/HF) in heart rate) and elevated blood pressure, as well as reduced baroreflex sensitivity (BRS). In contrast, those with higher BDNF levels (Dhigh) similar to controls, did not. Dlow animals persistent cardiovascular changes were abolished by acute inhibition of the dorsomedial nucleus of the hypothalamus (DMH). These cardiovascular changes were also prevented by chronic sub-cutaneous osmotic infusion of losartan, an angiotensin II type 1 receptor (AT
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2020
DOI: 10.1161/HYP.76.SUPPL_1.18
Abstract: Background: Orexin is a neuropeptide which can influence a wide range of physiological functions including blood pressure, sympathetic nervous system activity and arousal. Orexinergic signalling is suggested to contribute to the neurogenic hypertension in BPH/2J mice, based on the hypotensive response to the dual orexin receptor (OxR) antagonist, Almorexant, which was not observed in normotensive BPN/3J controls. Orexin is also known to influence the cardiovascular response to certain stressors. Thus, it is possible that orexin may also contribute to the exaggerated pressor response to stress that is reported in BPH/2J mice. Objective: To determine the contribution of orexin to the hypertension and exaggerated stress reactivity in BPH/2J wild type mice by comparing with BPH/2J Orexin homozygous knock out (BPH OxKO) mice. Methods: BPH OxKO (n=9) and BPH wild type (BPH WT) mice (n=6) were implanted with radiotelemetry probes to measure blood pressure (BP), heart rate (HR) and locomotor activity across the 24hr period and in response to restraint and dirty cage swap stressors. The BP responses to ganglion blocker pentolinium (5mg/kg, i.p.), was also measured. Results: There was no difference in average mean arterial pressure (MAP) over the 24hr period in BPH OxKO mice (131±1 vs 133±1mmHg, P =0.351), but there was a modest elevation in systolic AP (+4.5mmHg) exclusively during light period in BPH OxKO compared with BPH WT mice (145±2 vs 141±2mmHg, P .032). HR was comparable between strains ( P =0.160) and locomotor activity tended to be lower in BPH OxKO compared with BPH WT mice during the dark period (1.1±0.2 vs 1.7±0.3 units respectively, P =0.051). The pressor response to dirty cage swap stress was lower in BPH OxKO compared with BPH WT mice (22±1 vs 28±1mmHg respectively, P .001), as was the response to restraint stress (36±1 vs 40±2mmHg respectively, P .05). The depressor response to ganglion blockade was comparable between strains ( P =0.255). Conclusion: The present findings suggest that whilst orexin does not contribute to sympathetically mediated hypertension, it may play a role in the exaggerated cardiovascular response to stress and hyperactivity in BPH/2J mice.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Wiley
Date: 15-09-2015
Abstract: Orexin/hypocretin neurons are located in and around the perifornical hypothalamus. Disinhibition of this area in the anaesthetized preparation evokes cardiorespiratory changes that can be reduced to nearly half or more by systemic Almorexant, a dual receptor antagonist of the two known orexin receptors, Ox1R and Ox2R. It is not clear if these reductions result from the blockade of one receptor or both. To determine the contribution of the two receptors, we compared the effects of Almorexant to those of the selective Ox1R antagonist ACT335827 and the selective Ox2R antagonists EMPA and TCS-OX2-29. Bicuculline (20 pmol) was injected in the perifornical hypothalamus of urethane-anaesthetized rats before and after administration of the drugs (all 15 mg/kg, intravenously). The pressor, tachycardic and tachypneic responses to bicuculline were attenuated/reduced by ACT335827 (by 19%, ns 10%, ns and 24%, P < 0.01, respectively), EMPA (by 35% P < 0.01 6%, ns and 26% P < 0.05) and TCS-OX2-29 (by 13%, ns 10%, ns and 42%, P < 0.001). These reductions represented only a fraction of the reduction after Almorexant (by 43%, P < 0.001 42%, P < 0.001 and 65% P < 0.001). However, when the selective Ox1R and Ox2R antagonists were given in combination, the reductions were greater and closer to those of Almorexant (ACT335827 + EMPA, by 26%, P < 0.05 24%, P < 0.05 and 47%, P < 0.001 ACT335827 + TCS-OX2-29, by 40%, P < 0.01 26%, P < 0.001 and 59%, P < 0.0001). This was particularly clear with the tachypneic response. These results suggest that both orexin receptors contribute to the cardiorespiratory response evoked from the hypothalamus under anaesthesia. They are consistent with our previous study in the conscious animal.
Publisher: Elsevier BV
Date: 09-2011
Publisher: Elsevier BV
Date: 09-2007
Publisher: American Physiological Society
Date: 09-1994
DOI: 10.1152/JN.1994.72.3.1337
Abstract: 1. The contribution of the midbrain periaqueductal gray (PAG) to the central regulation of vocalization was investigated by analyzing the electromyographic (EMG) changes in respiratory, laryngeal, and oral muscles evoked by microinjection of D,L-homocysteic acid (DLH) in the PAG of unanesthetized, precollicular decerebrate cats. Moderate to large (6-40 nmol) doses of DLH evoked natural-sounding vocalization as well as increases in inspiratory depth and respiratory rate. 2. Two basic types of vocalization were evoked, each associated with a distinct and characteristic pattern of respiratory, laryngeal and oral EMG changes. Type A vocalization (voiced sounds such as howl/mew/growl) was characterized by excitation of the cricothyroid (CT) and thyro-arytenoid (TA) muscles, and inhibition of the posterior crico-arytenoid (PCA) muscle, whereas type B vocalization (unvoiced hiss sounds) was characterized by excitation of the PCA and TA muscles and no significant activation of the CT muscle. In addition, stronger expiratory (external oblique, internal oblique, internal intercostal) EMG increases were associated with type A responses, and larger increases in genioglossus and digastric muscle activity were associated with type B responses. 3. Microinjections of small doses of DLH (300 pmol-3 nmol), also evoked patterned changes in muscle activity (usually without audible vocalization) that, although of lower litude, were identical to those evoked by injections of moderate to large DLH doses. In no such experiments (175 sites) were in idual muscles activated by small dose injections of DLH into the PAG. Further, type A vocalization/muscle patterns were evoked from PAG sites caudal to those at which type B vocalization/muscle patterns were evoked. 4. Considered together these results indicate: that the PAG contains topographically separable groups of neurons that coordinate laryngeal, respiratory, and oral muscle patterns characteristic of two fundamental types of vocalization and that the underlying PAG organization takes the form of a representation of muscle patterns, rather than in idual muscles. 5. The patterns of EMG activity evoked by excitation of PAG neurons were strikingly similar to previously reported patterns of EMG activity characteristic of major phonatory categories in higher species, including humans (e.g., vowel phonation, voiceless consonant phonation). These findings raise the possibility that the sound production circuitry of the PAG could well be utilized by cortical and subcortical "language structures" to coordinate basic respiratory and laryngeal motor patterns that are necessary for speech.
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.AUTNEU.2016.08.015
Abstract: Autonomic dysreflexia is a common complication after high level spinal cord injury and can be life-threatening. We have previously shown that the acute transplantation of olfactory ensheathing cells into the lesion site of rats transected at the fourth thoracic spinal cord level reduced autonomic dysreflexia up to 8weeks after spinal cord injury. This beneficial effect was correlated with changes in the morphology of sympathetic preganglionic neurons despite the olfactory cells surviving no longer than 3weeks. Thus the transitory presence of olfactory ensheathing cells at the injury site initiated long-term functional as well as morphological changes in the sympathetic preganglionic neurons. The primary aim of the present study was to evaluate whether olfactory ensheathing cells survive after transplantation within the parenchyma close to sympathetic preganglionic neurons and whether, in this position, they still reduce the duration of autonomic dysreflexia and modulate sympathetic preganglionic neuron morphology. The second aim was to quantify the density of synapses on the somata of sympathetic preganglionic neurons with the hypothesis that the reduction of autonomic dysreflexia requires synaptic changes. As a third aim, we evaluated the cell type-specificity of olfactory ensheathing cells by comparing their effects with a control group transplanted with fibroblasts. Animals transplanted with OECs had a faster recovery from hypertension induced by colorectal distension at 6 and 7weeks but not at 8weeks after T4 spinal cord transection. Olfactory ensheathing cells survived for at least 8weeks and were observed adjacent to sympathetic preganglionic neurons whose overall number of primary dendrites was reduced and the synaptic density on the somata increased, both caudal to the lesion site. Our results showed a long term cell type-specific effects of olfactory ensheathing cells on sympathetic preganglionic neurons morphology and on the synaptic density on their somata, and a transient cell type-specific reduction of autonomic dysreflexia.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S0166-4328(03)00033-0
Abstract: Contextual conditioned fear in the rat is characterized by a freezing immobility associated with a marked increase in blood pressure, a slow increase in heart rate, and ultrasonic vocalizations. A previous Fos study also revealed a marked activation of the ventrolateral part of the periaqueductal gray (VLPAG) and a much smaller activation of its dorsal part (DPAG). Recent chemical blockade experiments indicate that the main role of the VLPAG in the response is to impose the immobility necessary for the expression of the freezing component. We now test the role of the DPAG to see if its small activation (as revealed by Fos) is of any functional significance in the contextual fear response. Large N-methyl-D-aspartate (NMDA) excitotoxic lesions that destroyed most of the DPAG were made in 10 rats. Another group of 10 rats had sham lesions with saline. The animals were then implanted with blood pressure telemetric probes, fear conditioned, and finally tested. There was no significant difference in the amount of freezing and in the blood pressure response between the two groups. However, there was a complete abolition of ultrasonic vocalizations and a significantly greater increase in heart rate in the DPAG-lesioned group. The effect on vocalization and heart rate may be explained by lesion of adjacent structures: the lateral PAG and the superior colliculus (baroreflex alteration), respectively. Thus, most of DPAG appears to play little role in the expression of the contextual fear response.
Publisher: Elsevier BV
Date: 12-1986
DOI: 10.1016/0166-4328(86)90068-9
Abstract: Microinjections of various doses (50-300 ng) of the nicotinic antagonist D-tubocurarine (TUBO) into the rat's medial hypothalamus (MH) or dorsal periaqueductal gray (PAG) produced flight reactions characterized by jumps. Two different types of flight reactions were produced depending on whether the drug was injected into the MH or into the PAG. MH injections provoked an increase in both locomotor activity and rearing together with well-oriented jumps. PAG injections provoked either freezing reactions or running with explosive jumps, but no increase in rearing. In addition, the rat exhibited an asymmetry in responsiveness to tactile stimulation. These reactions also differed depending on whether the drug was injected into the dorsal or ventral PAG. Behavioral reactions similar to those produced by TUBO were also produced by microinjection of the GABA receptor antagonist bicuculline into the same brain sites. Among the 4 putative cholinergic antagonists tested under the same conditions only alpha-bungarotoxin produced effects that were qualitatively similar to those induced by D-tubocurarine or bicuculline. Gallamine and hemicholinium produced tremor when injected into sites located near the ventricular system at either the MH or the PAG level, while vocalizations were only produced by PAG injections. Hexamethonium produced no marked effect. The hypothesis that flight reactions induced by D-tubocurarine or alpha-bungarotoxin do not result from their antinicotinic action but rather from a direct effect on GABAergic transmission is discussed.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.NEUROSCIENCE.2010.01.039
Abstract: The aim of this study was to test a possible role of A5 neurons in the expression of the pressor and tachycardic responses to conditioned fear and restraint, two forms of psychological stress. Previous Fos studies have shown that the C1 adrenergic neurons and spinally projecting neurons in the vasopressor region of the rostral ventrolateral medulla are not activated by these two stressors, suggesting that these cardiovascular changes may be mediated by other premotor sympathetic (presympathetic) cell groups. The same studies also revealed that the A5 noradrenergic group was one of the main presympathetic cell groups to be activated in response to these two stressors. Thus, we hypothesized that the A5 group could mediate these cardiovascular responses. Conditioned fear and restraint were tested in rats implanted with radiotelemetric probes before and after retrograde lesion with the selective toxin anti-dopamine-beta-hydroxylase-saporin bilaterally injected in the spinal cord at T2-T3. Six animals were selected that had the most extensive loss of spinally projecting catecholaminergic neurons: A5 (81%-95%) and rostral C1 (59%-86%, which would include most C1 bulbospinal neurons). However, despite this major loss of noradrenergic and adrenergic presympathetic neurons, the magnitude of the cardiovascular response to conditioned fear and restraint was the same before and after the lesion. Associated behavioural changes were not affected either. The results indicate that A5 presympathetic neurons are not essential for the expression of the tachycardic and pressor responses to conditioned fear and restraint. They also confirm that C1 bulbospinal neurons are not involved in these responses. The presympathetic neurons driving the tachycardic and pressor responses to conditioned fear and restraint must be elsewhere.
Publisher: Springer Science and Business Media LLC
Date: 24-03-2017
Publisher: Elsevier BV
Date: 08-2009
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1016/S1566-0702(02)00039-5
Abstract: This study investigates the contribution of the peripheral nervous system to the cardiovascular component of long lasting (40 min) conditioned fear responses to context. The conditioned fear response evoked by reexposure to a footshock chamber was tested 10 min after intravenous injection of either the nicotinic ganglion blocker chlorisondamine (0.6 mg/kg) or the alpha-adrenoceptor antagonist phentolamine (10 mg/kg) in six rats implanted with telemetric probes. Compared to saline controls, chlorisondamine did not change the behavioural component of the response (freezing, ultrasonic vocalizations) but almost completely abolished its cardiovascular component (mean arterial pressure and heart rate). Phentolamine also abolished the pressor response but increased the cardiac response, and ultrasonic vocalizations were reduced by half. The results indicate that the long lasting pressor response of conditioned fear to context is sympathetically mediated like the much shorter pressor response of conditioned fear to a discrete stimulus.
Publisher: Elsevier BV
Date: 08-2009
Publisher: American Physiological Society
Date: 04-2009
DOI: 10.1152/AJPREGU.90723.2008
Abstract: As with other forms of psychological stress, conditioned fear causes an increase in body temperature. The mechanisms underlying this stress-induced hyperthermia are not well understood, but previous research suggests that nonshivering thermogenesis might contribute, as it does during cold exposure. The major source of nonshivering thermogenesis in the rat is brown adipose tissue (BAT), and the largest BAT deposit in that species is in the interscapular area just below the skin. BAT is also under sympathetic control via β-adrenoceptors. If BAT contributes to fear-induced hyperthermia, then the interscapular skin should warm up faster than other skin areas, and this response should be suppressed by the β-adrenoceptor antagonist, propranolol. We tested this noninvasively by infrared thermography. In conscious rats, 30 min of contextual fear caused hyperthermia (as indicated by a +1.5°C increase in lumbar back skin temperature) and increased the difference in temperature between interscapular and lumbar back skin (TiScap − TBack) by +1°C. Propranolol (10 mg/kg ip) completely abolished this hyperthermia however, the TiScap-TBack increase was not reduced. In contrast, exposure to cold air (4°C) induced a +2.7°C increase in TiScap-TBack, which was reduced to +1°C after propranolol. The results show that conditioned fear-induced hyperthermia is of nonshivering origin and mediated by β-adrenoceptors, but interscapular BAT does not contribute to it and does not appear to be activated, either.
Publisher: Elsevier BV
Date: 09-2007
Publisher: Elsevier BV
Date: 02-2003
DOI: 10.1016/S0306-4522(02)00744-3
Abstract: We have previously shown that conditioned fear to context increases Fos expression in the caudal ventrolateral region of the periaqueductal gray in the rat. To understand the reason for this activation and its role in the expression of the contextual fear response, the ventrolateral periaqueductal gray was temporarily blocked with bilateral microinjections (0.4 microl) of the GABA agonist muscimol (0.2 mM) or the glutamate antagonist kynurenic acid (0.1 M). Cardiovascular changes and activity were recorded by radio-telemetry and the microinjections were made immediately before testing the conditioned response in the aversive context. Muscimol and kynurenic acid had the same effects: when compared to saline controls, freezing immobility and ultrasonic vocalizations were reduced and replaced by marked locomotor activity, and the increase in heart rate was enhanced however, the increase in arterial blood pressure remained the same. Interesting changes were also observed when animals were returned to the safe context of their home box after fear (recovery). Basically, the recovery response was either prevented or delayed: instead of returning to resting immobility, the rats remained agitated in their home box with a moderately elevated activity, heart rate and blood pressure. However, the effect of ventrolateral periaqueductal gray blockade on heart rate, arterial pressure and activity did not appear to be specific to the fear response or its recovery because they were also observed in animals returned to the safe context of their home box immediately after injection. The later response was also a recovery response from the milder stress of handling and the injection procedure.We discuss the results by arguing that the ventrolateral periaqueductal gray is involved in the immobility component of both the fear response and poststress recovery responses. To explain our interpretation we consider the findings in relation to the classic descending defence-arousal system and the hyporeactive-hypotensive immobility pattern that has been attributed to the ventrolateral periaqueductal gray. We propose that there is a dual activation of the defence-arousal system and of the ventrolateral periaqueductal gray during fear, with the ventrolateral periaqueductal gray acting as a brake on the defence-arousal system. The role of this brake is to impose immobility and hold off active defence responses such as fight and flight. The result of this combination of arousal and immobility is a hyperreactive freezing immobility associated with ultrasonic vocalizations, and a pressor response accompanied with a slow rise in heart rate. Basically, the animal is tense and ready for action but temporarily immobilised. The ventrolateral periaqueductal gray also acts to impose immobility during recovery however, this is without coactivation of the defence-arousal system. The result is a return to resting immobility, associated with a return to baseline blood pressure and heart rate. This is an active process that insures a faster and complete return to rest. We conclude that the ventrolateral periaqueductal gray is an immobility center involved not only in the fear response but also in poststress recovery responses.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Elsevier BV
Date: 2007
DOI: 10.1016/J.BRAINRES.2006.10.058
Abstract: The aim of this study was to test the role of the perifornical hypothalamus and adjacent areas in the behavioral and cardiovascular responses to two forms of stress, conditioned fear to context and restraint. Of particular interest was the role of the hypocretin (orexin) containing neurons in these responses. Rats implanted with radio-telemetric probes and fear conditioned to a context received bilateral injections of the neurotoxin hypocretin-2-saporin centered on the perifornical area. One week later, the animals were tested for conditioned fear to context and restraint while recording freezing, 22 kHz ultrasonic vocalizations, activity, mean arterial pressure and heart rate. Histological verification revealed that the lesions were not specific since virtually all the neurons within the injection area were lost. Nevertheless, these lesions, which were centered on the perifornical area, markedly reduced all recorded components of the contextual fear response (by 70%) but had no effect on the response to restraint. The lesions also caused a reduction in body weight and reduced the circadian rhythm of the recorded parameters. The results show (i) that hypocretin-2-saporin was not specific enough to produce lesions restricted to the hypocretin system, (ii) that neurons of the perifornical area are necessary for the expression of both the cardiovascular and behavioral components of conditioned fear to context, and (iii) that the same neurons are not necessary for the cardiovascular response to restraint. Thus, the perifornical hypothalamus is critical for some forms of stress but not others. We propose that it is a necessary relay for emotional responses in which the psychological component is stronger than the sensory component.
Publisher: Wiley
Date: 04-2013
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NEUROSCIENCE.2011.11.073
Abstract: The rostral medullary raphe region is an important target of hypothalamic orexin neurons however, little is known of the effect of orexin in this key autonomic and somatic premotor region. Here we tested the effect of orexin-A (3 and 30 pmol) microinjected in the medullary raphe, on heart rate (HR), mean arterial pressure (MAP), tail skin blood flow, body temperature, and behavior in freely moving, awake rats. HR, MAP, and body activity were recorded by radio-telemetry. Changes in tail skin blood flow and body temperature, as well as potential interscapular brown adipose tissue thermogenesis were recorded indirectly by infrared thermography of the skin of the tail, lumbosacral back, and interscapular back areas, respectively. Compared with saline, orexin-A (30 pmol) evoked significant and long lasting increases in HR (+99 bpm), MAP (+11 mmHg), and body activity (grooming, not locomotor activity). However, it did not reduce tail skin blood flow more than saline, and there was no significant increase in body temperature. A small, though significant, thermogenic effect was observed in the interscapular region, but this effect is more likely to have originated from activity in neck and shoulder muscles than brown adipose tissue. Thus, orexin projections to the rostral medullary raphe can mediate significant cardiovascular changes, but does not seem to affect tail skin vasomotor tone or brown adipose tissue in the awake rat. This important brainstem relay may contribute to the cardiovascular changes evoked by arousal and various forms of stress that are associated with activation of orexin neurons.
Publisher: Elsevier BV
Date: 04-2001
DOI: 10.1016/S0006-8993(01)02227-2
Abstract: Cardiovascular and behavioral responses were recorded in rats during exposure to cat odor. Rats were habituated to an open rectangular arena that contained a small enclosed wooden box in which they could hide. On day 1 of the experiment, after 30 min in the apparatus, rats were presented with a piece of fabric collar for 60 min. On day 2, rats were presented with an identical piece of fabric collar, except that it had been worn by a cat and therefore exuded cat odor. On day 3, rats were again presented with an unworn cat collar, to determine any conditioned responses to the environment or stimulus (collar) previously associated with cat odor. Results showed significantly increased blood pressure and decreased activity during exposure to cat odor as well as avoidance of the odor stimulus and an increase in vigilance and risk-assessment measures. No significant change in heart rate was found during cat odor exposure. On day 3, a transient increase in blood pressure was seen as well as reduced activity and a range of defensive behaviors. This suggests some conditioning of fear to a context in which cat odor had previously been experienced. Heart rate was also significantly decreased on day 3. A transient rise in blood pressure was also seen when the unworn cat collar was placed into the apparatus on day 3, suggesting a conditioned response to a stimulus that has been previously associated with cat odor. This study demonstrates that a natural stressful stimulus can induce both unconditioned and conditioned autonomic and behavioral responses.
Publisher: Elsevier BV
Date: 08-2013
Publisher: Elsevier BV
Date: 08-2004
Publisher: Society for Neuroscience
Date: 16-01-2019
DOI: 10.1523/JNEUROSCI.1815-18.2019
Abstract: Sensory problems such as neuropathic pain are common and debilitating symptoms in multiple sclerosis (MS), an autoimmune inflammatory disorder of the CNS. Regulatory T (Treg) cells are critical for maintaining immune homeostasis, but their role in MS-associated pain remains unknown. Here, we demonstrate that Treg cell ablation is sufficient to trigger experimental autoimmune encephalomyelitis (EAE) and facial allodynia in immunized female mice. In EAE-induced female mice, adoptive transfer of Treg cells and spinal delivery of the Treg cell cytokine interleukin-35 (IL-35) significantly reduced facial stimulus-evoked pain and spontaneous pain independent of disease severity and increased myelination of the facial nociceptive pathway. The effects of intrathecal IL-35 therapy were Treg-cell dependent and associated with upregulated IL-10 expression in CNS-infiltrating lymphocytes and reduced monocyte infiltration in the trigeminal afferent pathway. We present evidence for a beneficial role of Treg cells and IL-35 in attenuating pain associated with EAE independently of motor symptoms by decreasing neuroinflammation and increasing myelination. SIGNIFICANCE STATEMENT Pain is a highly prevalent symptom affecting the majority of multiple sclerosis (MS) patients and dramatically affects overall health-related quality of life however, this is a research area that has been largely ignored. Here, we identify for the first time a role for regulatory T (Treg) cells and interleukin-35 (IL-35) in suppressing facial allodynia and facial grimacing in animals with experimental autoimmune encephalomyelitis (EAE). We demonstrate that spinal delivery of Treg cells and IL-35 reduces pain associated with EAE by decreasing neuroinflammation and increasing myelination independently of motor symptoms. These findings increase our understanding of the mechanisms underlying pain in EAE and suggest potential treatment strategies for pain relief in MS.
Publisher: Oxford University Press
Date: 04-2011
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.NPEP.2009.12.012
Abstract: People with high level spinal cord injury (SCI) suffer from both hypotension and spontaneous hypertension due to loss of supraspinal control of spinal sympathetic outflow. Few reports have addressed whether any changes occur in central regulation of blood pressure (BP) and heart rat (HR) at the supraspinal level. Central tachykinin NK-1 and NK-3 receptors are located in many cardiovascular areas in the brain and are known to modulate BP and HR. This study examined the intracerebroventricular (i.c.v.) effects of the selective NK-1 receptor agonist [Sar(9), Met(O(2))(11)]SP (65pmol, n=6) and NK-3 receptor agonist senktide (650pmol, n=6) on mean arterial pressure (MAP) and HR before and after complete spinal cord transection at thoracic level 4 (T4). [Sar(9), Met(O(2))(11)]SP evoked increases in MAP and HR which were still present 4days after the T4 SCI. Further analysis using the beta(1)-adrenoceptor antagonist atenolol (10mgkg(-1)) revealed an increased contribution of HR in the MAP increase after SCI. For senktide, 2 and 5weeks after T4 SCI, the rise in MAP induced by senktide was significantly increased in magnitude and was similar to a normal response at 8weeks. These effects were accompanied by a bradycardia, which was still present and lified at 8weeks. Our results reveal a transient potentiation of the senktide-mediated MAP effect and a greater contribution of the HR in MAP increase by [Sar(9), Met(O(2))(11)]SP in T4 transected rats. Although the significance of these changes remains to be established. This suggest a reorganization of supraspinal mechanisms regulating BP and HR after a high level SCI. Central NK-1 and NK-3 receptors might therefore contribute to the maintenance of MAP following high thoracic SCI.
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.NEUROPHARM.2014.09.012
Abstract: Orexin contributes to the expression of the cardiovascular and behavioural response of some forms of stress, including novelty stress. Thus, Almorexant, a dual receptor antagonist that blocks the two known orexin receptors, Ox1R and Ox2R, reduces these responses. However, it is not known if the reduction results from blockade of one receptor only or both. To answer this question, the selective Ox1R antagonist ACT335827 and the selective Ox2R antagonist EMPA were injected intragastrically (300 mg/kg) or intraperitoneally (30 and 100 mg/kg) either alone or as a cocktail and compared to Almorexant in rats exposed to novelty stress. Cardiovascular and locomotor responses were recorded by radio-telemetry. Triple immunolabelling was also conducted to establish the distribution of Ox1R and Ox2R in sympathetic preganglionic neurons and orexin neurons. Intraperitoneal injections of ACT335827 (100 mg/kg) reduced the pressor and tachycardic but not the locomotor response of novelty (by 32% and 48%, respectively). Intraperitoneal injections of EMPA (100 mg/kg) only reduced the pressor response (42%). However when given together, ACT335827 and EMPA reduced all 3 components (65%, 60% and 57% of the tachycardic, pressor and locomotor responses, respectively) as Almorexant (100 mg/kg) did (69%, 87% and 72%, respectively). Triple immunolabelling revealed that sympathetic preganglionic neurons were mainly Ox1R positive only while orexin neurons were both Ox1R and Ox2R positive. This study shows that orexin's contribution to the cardiovascular and locomotor components of the novelty stress response is not mediated by one receptor alone, but by both receptors and at different levels of the neuraxis.
Publisher: Elsevier BV
Date: 10-2021
DOI: 10.1016/J.BBR.2021.113515
Abstract: The neuropeptide orexin-A (OX-A) has erse functions, including maintaining arousal, autonomic control, motor activity and stress responses. These functions are regulated at different terminal regions where OX-A is released. The current study examined the physiological and behavioural effects of OX-A microinjections into the central amygdala (CeA) under basal and stressed conditions in rats. When OX-A was microinjected into the CeA and the animals returned to the home-cage, heart rate and mean arterial pressure were increased compared to vehicle-injected controls. General activity of the animal was also increased, indicating that OX-A activity in CeA contributes to increased arousal. This outcome is similar to the effects of central intracerebroventricular infusions of OX-A, as well as the cardiovascular effects previously demonstrated at many of OX's efferent hypothalamic and brainstem structures. In a second study, animals were fear-conditioned to a context by delivery of electric footshocks and then animals were re-exposed to the conditioned context at test. When OX-A was microinjected at test, freezing behaviour was reduced and there was a corresponding increase in the animal's activity but no impact on the pressor and cardiac responses (i.e, blood pressure and heart rate were unchanged). This reduction in freezing suggests that OX-A activates amygdala neurons that inhibit freezing, which is similar to the actions of other neuropeptides in the CeA that modulate the appropriate defence response to fearful stimuli. Overall, these data indicate that the CeA is an important site of OX-A modulation of cardiovascular and motor activity, as well as conditioned freezing responses.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2020
DOI: 10.1038/S41467-020-16298-2
Abstract: Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic cl studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.
Publisher: Humana Press
Date: 2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2016
DOI: 10.1161/HYPERTENSIONAHA.115.07053
Abstract: BPH/2J mice are a genetic model of hypertension associated with an overactive sympathetic nervous system. Orexin is a neuropeptide which influences sympathetic activity and blood pressure. Orexin precursor mRNA expression is greater in hypothalamic tissue of BPH/2J compared with normotensive BPN/3J mice. To determine whether enhanced orexinergic signaling contributes to the hypertension, BPH/2J and BPN/3J mice were preimplanted with radiotelemetry probes to compare blood pressure 1 hour before and 5 hours after administration of almorexant, an orexin receptor antagonist. Mid frequency mean arterial pressure power and the depressor response to ganglion blockade were also used as indicators of sympathetic nervous system activity. Administration of almorexant at 100 (IP) and 300 mg/kg (oral) in BPH/2J mice during the dark-active period (2 hours after lights off) markedly reduced blood pressure (−16.1±1.6 and −11.0±1.1 mm Hg, respectively P .001 compared with vehicle). However, when almorexant (100 mg/kg, IP) was administered during the light-inactive period (5 hours before lights off) no reduction from baseline was observed ( P =0.64). The same dose of almorexant in BPN/3J mice had no effect on blood pressure during the dark ( P =0.79) or light periods ( P =0.24). Almorexant attenuated the depressor response to ganglion blockade ( P =0.018) and reduced the mid frequency mean arterial pressure power in BPH/2J mice ( P .001), but not BPN/3J mice ( P =0.70). Immunohistochemical labeling revealed that BPH/2J mice have 29% more orexin neurons than BPN/3J mice which are preferentially located in the lateral hypothalamus. The results suggest that enhanced orexinergic signaling contributes to sympathetic overactivity and hypertension during the dark period in BPH/2J mice.
Publisher: American Physiological Society
Date: 08-2016
DOI: 10.1152/AJPREGU.00021.2016
Abstract: Repeated social defeat in the rat induces long-lasting cardiovascular changes associated with anxiety. In this study, we investigated the effects of repeated social defeat on breathing. Respiratory rate was extracted from the respiratory sinus arrhythmia (RSA) peak frequency of the ECG in rats subjected to social defeat for 4 consecutive days. Respiratory rate was recorded under anesthesia 6 days (D+10) or 26 days (D+30) after social defeat. At D+10, defeated (D) rats spent less time in the open arms of the elevated plus maze test, had heavier adrenal glands, and displayed bradypnea, unlike nondefeated animals. At D+30, all signs of anxiety had disappeared. However, one-half of the rats still displayed bradypnea (DL rats, for low respiratory rate indicated by a lower RSA frequency), whereas those with higher respiratory rate (DH rats) had recovered. Acute blockade of the dorsomedial hypothalamus (DMH) or nucleus tractus solitarii (NTS) 5-HT3 receptors reversed bradypnea in all D rats at D+10 and in DL rats at D+30. Respiratory rate was also recorded in conscious animals implanted with radiotelemetric ECG probes. DH rats recovered between D+10 and D+18, whereas DL rats remained bradypneic until D+30. In conclusion, social stress induces sustained chronic bradypnea mediated by DMH neurons and NTS 5-HT3 receptors. These changes are associated with an anxiety-like state that persists until D+10, followed by recovery. However, bradypnea may persist in one-half of the population up until D+30, despite apparent recovery of the anxiety-like state.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Wiley
Date: 10-2009
DOI: 10.1111/J.1460-9568.2009.06952.X
Abstract: Hypocretin/orexin has a well-established role in wakefulness and in the maintenance of arousal. Because stress is associated with arousal, it has been proposed that hypocretin is also involved in stress. However, it is not clear if this is true for all forms of stress. To clarify this issue, we compared four conditions combining high arousal with no or low stress (wakefulness and exploration) or high stress (contextual fear and restraint) in the rat. We looked at Fos expression in hypocretin neurons, hypocretin-1 levels in cerebrospinal fluid and cardiovascular and behavioural changes after pharmacological blockade with the dual hypocretin receptor antagonist, almorexant. Fos expression in hypocretin neurons was highest with wakefulness and exploration, also high with fear but not significant with restraint. Hypocretin-1 levels were consistent with this pattern, although the differences were not as marked. Hypocretin receptor blockade with almorexant reduced the pressor, tachycardic and locomotor responses of wakefulness and exploration as well as the pressor and sympathetic component of the tachycardic response of fear. In contrast, almorexant did not reduce the pressor and tachycardic responses of restraint and nor did it reduce the pressor, tachycardic and locomotor responses of another stressor, i.e. cold exposure. Thus, hypocretin is not involved in all forms of stress. Comparison of the different conditions suggests that, regardless of stress, hypocretin involvement occurs when the arousal associated with the response includes increased attention to environmental cues. When it does, hypocretin will at least contribute to the cardiovascular response. The findings are of clinical relevance to some forms of psychological stress.
Publisher: Elsevier
Date: 2004
Publisher: Elsevier BV
Date: 09-2011
Publisher: American Physiological Society
Date: 15-01-2015
DOI: 10.1152/JAPPLPHYSIOL.00799.2014
Abstract: Recording of breathing frequency is a basic requirement for respiratory physiology. Usual techniques are invasive and constraining. Respiratory sinus arrhythmia (RSA) has recently been demonstrated to be a simple way to obtain respiration frequency at rest. In this study, we investigated whether this correlation is also observed during activity. We first compared RSA to the respiration frequency obtained in anesthetized rats using a pneumotachograph connected to the trachea (TRF). Data analyses using Passing and Bablok regression confirmed the absence of bias and proportional differences. Accordingly, the Bland-Altman plot did not show any significant differences in data sets. In a second experiment, we compared RSA to the respiration frequency obtained in freely moving rats using a subpleurally inserted telemetric catheter (PRF). Comparisons between RSA and PRF revealed no significant difference in determination of respiratory rate with the two methods, although the bias and confidence interval were greater when activity increased. This was, however, not the case during short episodes of sniffing-like tachypnea, during which no matching RSA peaks were observed. In conclusion, RSA frequency reflected regular respiration frequency independently of the level of activity and appears to be a good surrogate to usual techniques.
Publisher: Elsevier BV
Date: 11-1996
DOI: 10.1016/S0006-8993(96)00477-5
Abstract: In view of recent evidence for a role for the B subtype of cholecystokinin (CCKB) receptor in panic and anxiety, the distribution of CCKB receptors in the forebrain of a Rhesus macaca monkey was examined by receptor autoradiography employing [125I]D-Tyr25(Nleu28,31)-CCK25-33S. CCKB receptors were widely and topographically distributed in cortex. Other structures with notable labelling included the basal ganglia, presubiculum, amygdala, mamillary bodies, cerebellar cortex and pineal gland. The distribution of CCKB receptors further supports roles for this peptide in behavioural processes.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.AUTNEU.2010.05.011
Abstract: Spinal cord transection at T4 results in severe damage of the nervous tissue, with impairment of motor, sensory and autonomic functions. Transplantation of olfactory ensheathing cells (OECs) has the potential to improve these functions through a number of mechanisms, which include facilitation of regeneration and neuroprotection. For cardiovascular functions, we have previously shown that OECs reduce the duration of autonomic dysreflexia, without evidence of regeneration. To further understand the mechanisms underpinning this improvement, we have studied changes in selected morphological features (cavitation, non-cavity tissue loss, morphology of sympathetic preganglionic neurons and primary afferent fibre density) in the T4-transected rat spinal cord over 9 weeks, both in control and OEC-transplanted animals. T4 transection led to a number of structural changes: gradual formation of cavities, non-cavity tissue loss, a long-term increase in soma size of sympathetic preganglionic neurons and a temporary increase in the extent of their dendritic arbours, and an increase in the density of primary afferent fibres caudal to the lesion. OECs decreased the cavitation and normalised soma size of the sympathetic preganglionic neurons below the lesion, while increasing the extent of dendritic arbours in the preganglionic neurons above the lesion. Thus the OECs may contribute to the normalisation of the dysreflexic hypertension through tissue preservation and normalisation of the morphology of the preganglionic neurons caudal to the lesion, while enhancing the input on the rostral preganglionic neurons, whose vasomotor control remains intact. We hypothesise that these changes are mediated through secretion of soluble trophic factors by the transplanted OECs.
Publisher: Springer Science and Business Media LLC
Date: 04-1991
DOI: 10.1007/BF00230972
Publisher: Elsevier BV
Date: 09-2011
Publisher: MDPI AG
Date: 11-12-2017
DOI: 10.3390/IJMS18122681
Publisher: Elsevier BV
Date: 06-1992
DOI: 10.1016/0304-3940(92)90692-Z
Abstract: It is well established that the nucleus retroambigualis (NRA) of the cat contains a population of expiratory-related neurons. We report here that in the unanesthetized, decerebrate cat, microinjections of 300-900 pmol of D,L-homocysteic acid within the NRA evoked excitation of laryngeal as well as expiratory muscles, and often pressor responses. Moreover, vocalizations, which did not sound like normal feline vocalizations (i.e., hiss, howl, mew, growl), were evoked from a restricted region of the NRA, 1-3 mm caudal to the obex. The results indicate that in addition to its role in expiration: (i) the NRA plays an important role in the control of laryngeal muscles and the production of vocalization and (ii) that neurons in the NRA region can modulate arterial pressure.
Publisher: Elsevier BV
Date: 09-1988
DOI: 10.1016/0006-8993(88)90378-2
Abstract: Wheat germ agglutinin-horseradish peroxidase (WGA-HRP) injections were made at sites within a restricted portion of the midbrain periaqueductal grey region (PAG) of the cat at which microinjection of the excitant amino acid, D.L-homocysteic acid, elicits the strongest form of a defence reaction, including a hypertensive response. Among the revealed projections, significant anterograde labelling was found in a discrete region of the rostral ventrolateral medulla, the subretrofacial nucleus (SRF). In the cat, the SRF contains pressor neurones which project to the spinal preganglionic sympathetic outflow. The labelling was most marked ipsilaterally, although substantial contralateral labelling was also observed. To verify that the projection to the SRF originated from the restricted 'defence region' of the PAG, WGA-HRP or rhodamine-labelled microspheres were injected into physiologically-identified sites in the SRF. In all experiments, labelled neurones were found in the same restricted region of the PAG at which DLH injection evokes hypertension and behavioural signs of the defence reaction. The results are consistent with the hypothesis that a discrete cell group within the PAG mediates both somatic and autonomic components of the defence reaction and that the characteristic hypertensive response is mediated by a direct pathway from these PAG cells to pressor neurones in the SRF.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.NEUBIOREV.2016.06.044
Abstract: Orexin, the arousal peptide, originates from neurons located in an area of the dorsal hypothalamus well known for integrating defense responses and their cardiovascular component. Orexin neurons, which are driven in large part by the limbic forebrain, send projections to many regions in the brain, including regions involved in cardiovascular control, as far down as sympathetic preganglionic neurons in the spinal cord. Central injections of orexin evoke sympathetically mediated cardiovascular responses. Conversely, blockade of orexin receptors reduce the cardiovascular responses to acute stressors, preferentially of a psychological nature. More importantly, lasting upregulation of orexin signaling can lead to a hypertensive state. This can be observed in rats exposed to chronic stress as well as in strains known to display spontaneous hypertension such as the spontaneously hypertensive rat (SHR) or the hypertensive BPH/2J Schlager mouse. Thus, there is a link between orexin, stress and hypertension, and orexin upregulation could be a factor in the development of essential hypertension. Orexin receptor antagonists have anti-hypertensive effects that could be of clinical use.
Publisher: Cold Spring Harbor Laboratory
Date: 21-09-2017
DOI: 10.1101/191841
Abstract: The midbrain periaqueductal gray (PAG) coordinates the expression and topography of defensive behaviors to threat and also plays an important role in Pavlovian fear learning itself. Whereas the role of PAG in expression of defensive behavior is well understood, the relationship between activity of PAG neurons and fear learning, the exact timing of PAG contributions to learning during the conditioning trial, and the contributions of different PAG columns to fear learning are poorly understood. We assessed the effects of optogenetic inhibition of lateral (LPAG) and ventrolateral (VLPAG) PAG neurons on fear learning. Using adenoassociated viral vectors expressing halorhodopsin (eNpHR3.0), we show that brief optogenetic inhibition of LPAG or VLPAG during delivery of the shock unconditioned stimulus (US) augments acquisition of contextual or cued fear conditioning and we also show that this inhibition augments post-encounter defensive responses to a non-noxious threat. Taken together, these results show that LPAG and VLPAG serve a key role in regulation of Pavlovian fear learning at the time of US delivery. These findings provide strong support for existing models which state that LPAG and VLPAG contribute to a fear prediction error signal determining variations in the effectiveness of the aversive US in supporting learning.
Publisher: SAGE Publications
Date: 18-05-2009
Abstract: Background. Weight-supported treadmill training is an emerging rehabilitation method used to improve locomotor ability in patients with spinal cord injury (SCI). However, little research has been undertaken to test the effect of such training on other consequences of SCI, such as neuropathic pain and autonomic dysfunction. Objective. This study investigates the effects of chronic treadmill training on the development of autonomic dysreflexia (AD), a form of cardiovascular dysfunction common in patients with cervical or high thoracic injury. Methods. Treadmill training commenced in adult male rats (n = 11) 3 days following complete T4 transection, whereas a sedentary SCI group (n = 9) and an intact group (n = 6) had no intervention. Treadmill training (up to 0.4 m/s) lasted for 10 min/d 5 days a week, for 6 weeks. Weekly measurements of locomotor ability (BBB scale), baseline mean arterial pressure, and heart rate were made, as were cardiovascular responses to training and colorectal distension (to trigger AD). Results. Treadmill training improved BBB scores from 2 weeks post-transection onward ( P = .010). However, it increased AD, resulting in augmented pressor responses from 2 to 6 weeks post-transection ( P = .029). Comparison of the vascular response to phenylephrine under ganglionic blockade showed an enhanced vasoconstrictor response in the renal vasculature of trained SCI animals. Immunohistochemical comparison of the L1—L6 spinal cord segments showed an increased area of CGRP immunoreactivity in the dorsal horn (lamina III/IV) of treadmill-trained SCI compared with intact and sedentary SCI animals. Conclusions. These results suggest that treadmill training exaggerated AD responses perhaps through a combination of enhanced vascular reactivity and central plasticity.
Publisher: Springer US
Date: 1995
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-1994
Publisher: Wiley
Date: 04-2019
Publisher: Elsevier BV
Date: 11-2015
Publisher: Wiley
Date: 05-2005
DOI: 10.1111/J.1460-9568.2005.04073.X
Abstract: Infrared thermography was used to image changes in cutaneous temperature during a conditioned fear response to context. Changes in heart rate, arterial pressure, activity and body (i.p.) temperature were recorded at the same time by radio-telemetry, in addition to freezing immobility. A marked drop in tail and paws temperature (-5.3 and -7.5 degrees C, respectively, down to room temperature), which lasted for the entire duration of the response (30 min), was observed in fear-conditioned rats. In sham-conditioned rats, the drop was on average half the magnitude and duration. In contrast, temperature of the eye, head and back increased (between + 0.8 and + 1.5 degrees C), with no difference between the two groups of rats. There was a similar increase in body temperature although it was slightly higher and delayed in the fear-conditioned animals. Finally, ending of the fear response was associated with a gradual decrease in body temperature and a rebound increase in the temperature of the tail (+ 3.3 degrees C above baseline). This study shows that fear, and to some extent arousal, evokes a strong cutaneous vasoconstriction that is restricted to the tail and paws. This regionally specific reduction in blood flow may be part of a preparatory response to a possible fight and flight to reduce blood loss in the most exposed parts of the rat's body in case of injury. The data also show that the tail is the main part of the body used for dissipating internal heat accumulated during fear once the animal has returned to a safe environment.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2009
Publisher: Wiley
Date: 04-2011
Publisher: American Physiological Society
Date: 15-11-2012
DOI: 10.1152/AJPREGU.00263.2012
Abstract: Orexin neurons form a restricted group in the dorsal hypothalamus. The group is centered on the perifornical area within the classic hypothalamic defense area, an area which when activated produces marked cardiovascular and respiratory effects. Central administration of orexin can produce cardiorespiratory effects, but the extent to which orexin contributes to such responses evoked from the perifornical hypothalamus is not clear. To determine this, we used the dual orexin receptor antagonist Almorexant to challenge the cardiorespiratory effects evoked by disinhibition of the perifornical hypothalamus. Bicuculline (10 and 20 pmol) was microinjected in the perifornical area before and after administration of Almorexant (15 mg/kg iv) or vehicle in urethane-anesthetized rats. Almorexant significantly reduced the pressor, tachycardic, renal sympathoexcitatory, and tachypneic responses to bicuculline (10 pmol, by 55%, 53%, 28%, 77% 20 pmol, by 54%, 27%, 51%, 72%, respectively). Reductions of similar magnitude were observed with bicuculline microinjections centered on more caudal sites just peripheral to the orexin neuron group, which would likely have activated fewer orexin neurons. In contrast, Almorexant had no effect on the cardiorespiratory response of the chemoreflex (sodium cyanide injection) or the sympathetic component of the baroreflex. Thus orexin makes a major contribution to the cardiorespiratory response evoked from the perifornical area even though orexin neurons represent only a fraction of the output of this area. Orexin neurons may also mediate cardiorespiratory responses from non-orexin neurons in the caudal hypothalamus. However, under resting conditions, blockade of orexin receptors does not affect the chemo- and baroreflexes.
Publisher: Frontiers Media SA
Date: 22-09-2016
Publisher: Elsevier
Date: 1991
Publisher: American Physiological Society
Date: 08-2009
DOI: 10.1152/AJPREGU.00232.2009
Abstract: 5-HT 1A agonists given systemically are known to produce anxiolytic effects. In addition, a growing body of research is showing that those compounds also have central sympathoinhibitory properties. Since emotional arousal gives rise to sympathetic activation, it is not clear whether systemic treatment with a 5-HT 1A agonist reduces the sympathetic response to emotional stress primarily by a direct action on sympathetic-related sites in the brain or indirectly through reducing anxiety. To test this, we compared the effect of intraperitoneal injections of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT 0.05 and 0.25 mg/kg), a preferential 5-HT 1A agonist, or vehicle on the cardiovascular responses to four stressors known to produce sympathetic activation, three being emotional stressors, and one physiological. In conscious rats, 30-min exposure to either a neutral context, a fear-conditioned context, or to restraint stress led to increases in heart rate and blood pressure, which were attenuated by 8-OH-DPAT. In contrast, the same treatment did not reduce the cardiovascular response to 30-min cold exposure (4°C). The results suggest that 8-OH-DPAT acts preferentially on limbic, rather than central, autonomic sites. Hence, doses of 5-HT 1A agonists, which are just sufficient to produce anxiolysis, are not enough to cause true sympathoinhibition.
Publisher: Wiley
Date: 23-07-2008
DOI: 10.1111/J.1460-9568.2008.06351.X
Abstract: Conditioned fear to context, a pure form of psychological stress, is associated with sympathetically mediated changes including a marked hypertension. To identify the possible premotor sympathetic neurons mediating these changes, we conducted double-immunolabelling experiments combining fear-induced Fos with retrograde tracing from the thoracic cord (T2-L1). Presympathetic groups showing the greatest increase in the proportion of spinally projecting cells double-labelled with Fos compared with resting controls were the perifornical area (PeF 22.7% vs. 0.4%) and paraventricular nucleus (Pa 10.5% vs. 0.2%) in the hypothalamus, and the A5 noradrenergic group (33.6% vs. 0.2%) in the pons. In contrast, there was only a small increase in the presympathetic groups of the rostral ventral medulla, including the lateral paragigantocellular group (LPGi 4.3% vs. 0.5%), raphe magnus and pallidus (1.1% vs. 0.6% and 1.8% vs. 0.5%), and the vasopressor group of the rostral ventrolateral medulla (RVLM 1.9% vs. 0.8%). PeF, Pa, A5 and LPGi accounted for 21, 15, 16 and 6% of all the double-labelled cells, respectively, and RVLM for only 1%. Double-immunolabelling of Fos and tyrosine hydroxylase confirmed that many A5 neurons were activated (19%) and that practically no C1 neurons in RVLM were (1.3%). The results suggest that the main premotor sympathetic drive of the fear response comes from hypothalamic (PeF and Pa) and A5 neurons that project directly to the thoracic cord and bypass medullary presympathetic groups, and that the vasopressor premotor sympathetic neurons of the RVLM are unlikely to mediate the hypertensive pressure response of contextual fear.
Publisher: Elsevier BV
Date: 06-2006
DOI: 10.1016/J.PHYSBEH.2006.03.007
Abstract: Rats were subject to daily injections of morphine or saline and were then allowed to spontaneously withdraw from morphine for 4 days. Mean arterial blood pressure (MAP) and heart rate (HR) were recorded continuously, via radiotelemetry, during the development of, and recovery from, opiate dependence. Injections of morphine produced pronounced and prolonged increases in MAP and HR which increased as morphine dose increased. There were also significant increases in MAP during the 19-23 h period after each morphine injection indicating the presence of withdrawal. Spontaneous withdrawal from morphine was associated with a pronounced (20% increase from baseline) and prolonged (72 h) increase in MAP. MAP returned to baseline levels 72-96 h after last morphine exposure. These results show that intermittent injections of morphine, and spontaneous withdrawal from these injections, are associated with profound alterations in cardiovascular function and confirm the usefulness of radiotelemetry for studying opiate dependence.
Publisher: Elsevier BV
Date: 12-1993
DOI: 10.1016/0166-4328(93)90088-8
Abstract: Recent findings suggest that the periaqueductal gray (PAG) can be sub ided on the basis of its anatomical connections and functional representation of cardiovascular and behavioral functions. This new scheme of sub ision postulates the existence of 4 major longitudinal columns located dorsomedial, dorsolateral, lateral and ventrolateral to the aqueduct. Attention has focussed on the lateral and ventrolateral columns, because they contain topographically distinct groups of neurons whose activation results in different forms of defensive or protective reactions. Reactions evoked from the lateral PAG column are associated with somatomotor and autonomic activation and are characteristic of an organism's response to superficial or cutaneous noxious stimuli, whereas reactions evoked from the ventrolateral PAG column are associated with somatomotor and autonomic inhibition and appear to correspond to an organism's response to deep or visceral noxious stimuli. Furthermore, the neurons of these two columns possess some degree of somatotopic and viscerotopic organization and send axon collaterals to multiple targets in the medulla. This model of PAG neuronal organization outlines the basic architectural features of a network involved in the coordinated expression of certain types of defensive rotective reactions.
Publisher: Elsevier BV
Date: 03-2000
DOI: 10.1016/S0006-8993(00)02029-1
Abstract: This study compares the time course of the cardiovascular changes (mean arterial blood pressure, heart rate) and behavioral changes (freezing, rearing, grooming and activity) evoked by 30 min long exposures to a footshock chamber before and after conditioning with footshocks. The main finding is that the conditioned fear evoked by re-exposure to the footshock chamber after conditioning is associated with a prolonged freezing response, a marked rise in mean arterial pressure (+35 mm Hg above a resting baseline of 105 mm Hg) and a delayed rise in heart rate. The pattern of behavioral and cardiovascular changes is the same as with conditioned fear to a discrete stimulus but the effect is a lot longer.
Publisher: Springer US
Date: 1991
Publisher: Elsevier BV
Date: 11-2015
Publisher: American Psychological Association (APA)
Date: 08-2016
DOI: 10.1037/BNE0000151
Abstract: Rodents display characteristic defense responses to predators that are influenced by predatory imminence. The midbrain periaqueductal gray (PAG) serves an important role controlling these responses. The most influential model states that variations in defensive topography are due to distinct PAG regions: ventrolateral PAG (VLPAG) controls postencounter defense, such as freezing and immobility, whereas lateral PAG (LPAG) controls circa-strike defense, such as escape and flight. Here we used channel rhodopsin (ChR2) stimulation to probe the structure of defensive behavior controlled by LPAG and VLPAG. Suprathreshold LPAG stimulation evoked circa-strike defense that was replaced by freezing at stimulation offset. Suprathreshold VLPAG stimulation evoked postencounter--freezing and immobility--but never circa-strike defense. More interestingly, the topography of defensive behavior evoked from LPAG scaled with variations in 465 nm light power. As light power increased, LPAG animals expressed the full defensive syntax of freezing then activity then flight characteristic of increasing predatory imminence. In contrast, the frequency, not topography, of defensive behavior evoked from VLPAG scaled with variations in light power. These findings suggest that LPAG and VLPAG can control variations in defense with increasing predatory imminence in 2 ways. First, consistent with past models, topographical variation can be assembled from different defensive responses controlled by the LPAG (circa-strike) and VLPAG (postencounter). Second, topographical variation can be assembled from variations in LPAG activity itself. (PsycINFO Database Record
Publisher: SAGE Publications
Date: 28-09-2017
Abstract: Psychogenic non-epileptic seizures (PNES) are a nonspecific, umbrella category that is used to collect together a range of atypical neurophysiological responses to emotional distress, physiological stressors and danger. Because PNES mimic epileptic seizures, children and adolescents with PNES usually present to neurologists or to epilepsy monitoring units. After a comprehensive neurological evaluation and a diagnosis of PNES, the patient is referred to mental health services for treatment. This study documents the diagnostic formulations – the clinical formulations about the probable neurophysiological mechanisms – that were constructed for 60 consecutive children and adolescents with PNES who were referred to our Mind-Body Rehabilitation Programme for treatment. As a heuristic framework, we used a contemporary reworking of Janet’s dissociation model: PNES occur in the context of a destabilized neural system and reflect a release of prewired motor programmes following a functional failure in cognitive-emotional executive control circuitry. Using this framework, we clustered the 60 patients into six different subgroups: (1) dissociative PNES (23/60 38%), (2) dissociative PNES triggered by hyperventilation (32/60 53%), (3) innate defence responses presenting as PNES (6/60 10%), (4) PNES triggered by vocal cord adduction (1/60 2%), (5) PNES triggered by activation of the valsalva manoeuvre (1/60 1.5%) and (6) PNES triggered by reflex activation of the vagus (2/60 3%). As described in the companion article, these diagnostic formulations were used, in turn, both to inform the explanations of PNES that we gave to families and to design clinical interventions for helping the children and adolescents gain control of their PNES.
Publisher: Springer US
Date: 1991
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.AUTNEU.2009.10.001
Abstract: Autonomic dysreflexia is a common complication in high spinal cord injury and can result in serious consequences and death. Here we have examined the effect of acute transplantation of olfactory ensheathing cells on cardiovascular functions in rats. After T4 transection, radio-telemetric recording in conscious animals was used to study blood pressure and heart rate at rest and during autonomic dysreflexia for up to 8 weeks post-injury. Olfactory ensheathing cells from syngeneic rats were transplanted at the injury site control animals received culture medium only. At the study end point, we examined morphometric features of sympathetic preganglionic neurons above and below the injury. T4 transection resulted in a fall in resting mean arterial pressure and an increase in resting heart rate. Colorectal distension, used to trigger autonomic dysreflexia, caused episodic hypertension and bradycardia. Although the cell transplantation had no effect on resting cardiovascular parameters, it led to a significantly faster recovery from hypertension, with the recovery time shortened by approximately 25%. The transection resulted in an increase in soma size of sympathetic preganglionic neurons above and below the injury. OEC transplantation normalised this change below the injury and increased dendritic length of preganglionic neurons above the injury, compared to controls. It has been proposed that changes in sympathetic preganglionic neurons following spinal cord transection may be related to the development of autonomic dysreflexia. Our results suggest that olfactory ensheathing cells may alter the morphology of these neurons, and hence modify their activity in the neuronal networks responsible for the dysreflexic reaction.
Publisher: American Physiological Society
Date: 06-2009
DOI: 10.1152/JAPPLPHYSIOL.00095.2009
Abstract: Subjects with severe chronic spinal cord injury (SCI) are prone to hypothermia when they are exposed to relatively low environmental temperatures that are normally well tolerated by healthy in iduals. This impaired thermoregulation is presumably due to disconnection of territories below the SCI from supraspinal thermoregulatory centers. However, it is not known how these territories respond to low temperatures. Using a complete transection at T 11 in rats, we examined the responses of the tail to cold (6–9°C) by measuring changes in tail blood flow and skin temperature weekly for 8 wk after SCI. Despite no significant change in baseline mean flow or temperature in the tail, the transection effectively removed the sympathetically mediated supraspinal control of the tail vasculature, since the litude of the pulse flow was markedly increased and the natural variations of the mean flow were almost abolished. As expected, the cold challenge before SCI caused a marked drop in mean flow, pulse litude, and temperature of the tail. Surprisingly, the drops in mean blood flow and temperature were observed after SCI, although the decrease in flow was slower and the pulse litude was not reduced. The results suggest that the cutaneous vasculature of the tail is sensitive to cold and will constrict, despite disconnection from supraspinal centers. This local effect is slow but may be sufficient to maintain some level of thermoregulation to cold. Without this vascular reaction, the effects of SCI on temperature regulation to cold would probably be much worse.
Publisher: Elsevier BV
Date: 1988
DOI: 10.1016/0006-8993(88)91465-5
Abstract: Unilateral microinjections (0.20 microliter) of the excitatory amino acids (EAA), L-aspartate (ASP), D,L-homocysteate (DLH) or kainate (KA) were made into the midbrain of freely moving cats. Injections of DLH (20 nmol) or ASP (200 nmol) made within the midbrain periaqueductal grey matter (PAG) consistently elicited a threat display characteristic of defensive behaviour (i.e., pupillary dilatation, piloerection, retraction of the ears, sideways backing, arching of the back, hissing, howling, growling), whereas injections of DLH or ASP made in the tegmentum bordering the PAG did not elicit such behaviour. Injections of KA (940 pmol) made within the PAG, but not the tegmentum, elicited not only a threat display but also directed attack (striking with unsheathed claws and biting). As injections of EAA depolarize cell bodies, but not axons, the results suggest that a population of neurones whose excitation elicits all of the behavioural signs of defence, including directed attack, is found within the PAG. Histology indicated that the region of the PAG from which the defence reaction was elicited was not confined to any PAG subnucleus. Rather, the 'defence region' of the PAG formed a cylindrical column lateral to the midbrain aqueduct, approximately 1.5 mm in diameter and 5.0 mm in length, the rostral end of which lay dorsal to the caudal end. Further, it was found that EAA microinjections made in different portions of the defence region of the PAG elicited defence reactions characterised by different patterns of vocalization and differing intensities of display. It was also observed following unilateral injection of KA into the PAG that defence reactions, including attack, were elicited by approach in the visual hemifield or touch of the body contralateral, but not ipsilateral, to the injection site. The asymmetry of the defence reaction was not due to any obvious ipsilateral motor impairment and thus suggests that the PAG mediation of the defence reaction, in addition to controlling the outflow to the somatic and autonomic motor systems, also affects sensory processing.
Publisher: Elsevier BV
Date: 02-1997
DOI: 10.1016/S0306-4522(97)83047-3
Abstract: Immunohistochemical detection of Fos was used to determine which regions of the periaqueductal gray are activated during conditioned fear to a context in the rat. More specifically, the aim of the study was to test the role of its lateral and ventrolateral columns in freezing behaviour during fear. Conditioned fear was evoked by re-exposing rats to the same footshock chamber in which they had received footshocks 4 h earlier. Conditioned Re-exposed rats were compared to Not Conditioned Re-exposed and Conditioned Not Re-exposed rats. Freezing was observed in the Conditioned-Re-exposed group only. It was associated with an overall increase in Fos expression in the entire periaqueductal gray that was significantly greater than in the two other groups. The largest and most significant increase in Fos immunoreactivity was found in the ventrolateral column (especially in its caudal part), whereas only a moderate increase was found in the lateral column. The present results argue in favour of the ventrolateral column as the region of the periaqueductal gray that is preferentially involved in expression of conditioned fear. As previous lesion studies suggested, the ventrolateral periaqueductal gray may play a role in mediating the immobility component of freezing induced by fear. Other lines of evidence suggest that it may also play a role in mediating the quiescence immobility associated with deep pain. We propose that the ventrolateral column of the periaqueductal gray acts as an integrating centre mediating behavioural inhibition.
Publisher: Elsevier BV
Date: 02-2012
Publisher: Wiley
Date: 04-2017
Publisher: Elsevier
Date: 2012
No related grants have been discovered for Pascal Carrive.