Kathryn Baker

Timing is everything: Developmental differences in the effect of chronic corticosterone exposure on extinction retention.

Publisher: American Psychological Association (APA)

Date: 10-2019

DOI: 10.1037/BNE0000326

Abstract: Adolescence is noted as a time of "storm and stress." In this developmental stage both rodents and humans exhibit an impairment in the extinction of learned fear however, this impairment can be alleviated, at least in rodents, by increasing the amount of extinction training given or by administering the partial NMDA receptor agonist D-Cycloserine. In the present study we explored whether the benefits of these treatments would be reduced by chronic exogenous corticosterone (a commonly studied stress-related hormone). In 2 experiments, adolescent rats were given pairings of a white noise and shock (acquisition) and then given extinction training (white noise presented alone). In Experiment 1, adolescents exhibited impaired extinction retention even after 2 days of extinction training if they had been exposed to corticosterone in adolescence but not if the exposure occurred when they were juveniles. In Experiment 2, exposure to exogenous corticosterone in adolescence, but not during the juvenile period, reduced the efficacy of the pharmacological adjunct D-Cycloserine at enhancing extinction retention after 1 day of extinction training. Taken together, the results support the idea that adolescence is a time of particular susceptibility to elevated levels of the stress hormone corticosterone. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The development of perineuronal nets around parvalbumin gabaergic neurons in the medial prefrontal cortex and basolateral amygdala of rats.

Publisher: American Psychological Association (APA)

Date: 08-2017

DOI: 10.1037/BNE0000203

Abstract: Perineuronal nets (PNNs) are extracellular matrix structures that preferentially surround mature GABAergic neurons that express the calcium-binding protein parvalbumin (PV). It has been suggested that aberrant PNN formation in humans may contribute to psychological disorders, many of which emerge during childhood and adolescence. The present experiment investigated the normative developmental trajectory of PNN formation in the medial prefrontal cortex (mPFC) and basolateral amygdala (BLA) in juvenile (P24), adolescent (P35-36), and adult (∼P70) rats. Dual-immunofluorescence staining revealed that there was a marked increase in the number of PNNs in both the prelimbic and infralimbic regions of the mPFC across the transition from the juvenile to adolescent period. Although there were no differences in the number of PV neurons across age groups, adolescent and adult rats had more PNNs surrounding PV neurons than juveniles. In contrast to the mPFC, juvenile and adolescent rats had similar total numbers of PNNs in the BLA, and total numbers of PNNs were even higher in adults in this region. In the BLA, adults had more PNNs around non-PV cells whereas the number of PV cells with PNNs did not differ across ages. However, expression patterns differed within subregions of the BLA such that adults had the most PNNs around both PV and non-PV cells in the lateral nucleus, with no age differences observed in the basal nucleus. These findings demonstrate that the juvenile to adolescent developmental period is an important time for the formation of prefrontal PNNs and the maturation of PV inhibitory neurons. (PsycINFO Database Record

A ryanodine receptor agonist promotes the consolidation of long-term memory in young chicks

Publisher: Elsevier BV

Date: 05-01-2010

DOI: 10.1016/J.BBR.2009.08.026

Abstract: Young chicks were trained on a weakly reinforced variant of a single-trial discrimination avoidance task which typically fails to consolidate the long-term memory stage. The ryanodine receptor (RyR) agonist 4-chloro-m-cresol (500 microM, i.c.) persistently promoted high retention until at least 24 h post-training when administered between the time of training and 20 min post-training. The consolidation of the long-term memory stage by RyR activation implicates intracellular calcium release in triggering long-term memory.

A window of vulnerability: Impaired fear extinction in adolescence

Publisher: Elsevier BV

Date: 09-2014

DOI: 10.1016/J.NLM.2013.10.009

Abstract: There have been significant advances made towards understanding the processes mediating extinction of learned fear. However, despite being of clear theoretical and clinical significance, very few studies have examined fear extinction in adolescence, which is often described as a developmental window of vulnerability to psychological disorders. This paper reviews the relatively small body of research examining fear extinction in adolescence. A prominent finding of this work is that adolescents, both humans and rodents, exhibit a marked impairment in extinction relative to both younger (e.g., juvenile) and older (e.g., adult) groups. We then review some potential mechanisms that could produce the striking extinction deficit observed in adolescence. For ex le, one neurobiological candidate mechanism for impaired extinction in adolescence involves changes in the functional connectivity within the fear extinction circuit, particularly between prefrontal cortical regions and the amygdala. In addition, we review research on emotion regulation and attention processes that suggests that developmental changes in attention bias to threatening cues may be a cognitive mechanism that mediates age-related differences in extinction learning. We also examine how a differential reaction to chronic stress in adolescence impacts upon extinction retention during adolescence as well as in later life. Finally, we consider the findings of several studies illustrating promising approaches that overcome the typically-observed extinction impairments in adolescent rodents and that could be translated to human adolescents.

Does maternal separation accelerate maturation of perineuronal nets and parvalbumin-containing inhibitory interneurons in male and female rats?

Publisher: Elsevier BV

Date: 02-2020

DOI: 10.1016/J.DCN.2020.100905

d-Lactate inhibition of memory in a single trial discrimination avoidance task in the young chick

Publisher: Elsevier BV

Date: 10-2007

DOI: 10.1016/J.NLM.2007.06.004

Abstract: L-Lactate is a metabolite possibly able to meet some neuronal energy demands. However, a clear role for L-lactate in behaviour remains elusive. Administration of the inactive isomer D-lactate (1.75 mM ic), immediately post-training, resulted in a persistent retention loss from 40 min post-training when used in conjuction with a single trial discrimination avoidance task designed for the young chick. Furthermore, 1mM noradrenaline (ic) administered 20 min post-training overcame the retention loss induced by D-lactate. Although not directly demonstrated in the current study, it is plausible that D-lactate inhibited memory processing by competing with L-lactate for uptake into neurons. The time of onset of the retention loss induced by D-lactate is in accord with findings where the action of noradrenaline is inhibited. The successful challenge of D-lactate inhibition by a high concentration of noradrenaline may suggest a relationship by some unidentified mechanism.

Elucidating the mechanisms of fear extinction in developing animals: a special case of NMDA receptor-independent extinction in adolescent rats.

Publisher: Cold Spring Harbor Laboratory

Date: 15-03-2018

DOI: 10.1101/LM.047209.117

Abstract: NMDA receptors (NMDARs) are considered critical for the consolidation of extinction but recent work challenges this assumption. Namely, NMDARs are not required for extinction retention in infant rats as well as when extinction training occurs for a second time (i.e., reextinction) in adult rats. In this study, a possible third instance of NMDAR-independent extinction was tested. Although adolescents typically exhibit impaired extinction retention, rats that are conditioned as juveniles and then given extinction training as adolescents (JuvCond-AdolesExt) have good extinction retention. Unexpectedly, this good extinction retention is not associated with an up-regulation of a synaptic plasticity marker in the medial prefrontal cortex, a region implicated in extinction consolidation. In the current study, rats received either the noncompetitive NMDAR antagonist MK801 (0.1 mg/kg, s.c.) or saline before extinction training. In several experiments, rats conditioned and extinguished as juveniles, adolescents, or adults exhibited impaired extinction retention after MK801 compared to saline, but this effect was not observed in JuvCond-AdolesExt rats. Further experiments ruled out several alternative explanations for why NMDAR antagonism did not affect extinction retention in adolescents extinguishing fear learned as a juvenile. These results illustrate yet another circumstance in which NMDARs are not required for successful extinction retention and highlight the complexity of fear inhibition across development.

Pharmacological evidence that a failure to recruit NMDA receptors contributes to impaired fear extinction retention in adolescent rats

Publisher: Elsevier BV

Date: 09-2016

DOI: 10.1016/J.NLM.2016.10.014

Abstract: Adolescents, both humans and rodents, exhibit a marked impairment in extinction of fear relative to younger and older groups which could be caused by a failure to efficiently recruit NMDA receptors (NMDARs) in adolescence. It is well-established that systemic administration of NMDAR antagonists (e.g., MK801) before extinction training impairs the retention of extinction in adult and juvenile rodents, but it is unknown whether this is also the case for adolescents. Therefore, in the present study we investigated the effect of pharmacologically manipulating the NMDAR on extinction retention in adolescent rats. When extinction retention is typically impaired (i.e., after one session of extinction training) adolescent male rats given d-cycloserine (a partial NMDAR agonist) showed enhanced extinction retention relative to saline-treated animals while animals given MK801 (a non-competitive antagonist) did not exhibit any further impairment of extinction retention relative to the controls. In a further two experiments we demonstrated that when two sessions of extinction training separated by either 4 or 24h intervals were given to adolescent rats, saline-treated animals exhibited good extinction retention and the animals given MK801 before the second session exhibited impaired extinction retention. These findings suggest that extinction in adolescence does not initially involve NMDARs and this is a likely mechanism that contributes to the impaired fear inhibition observed at this age. However, NMDARs appear to be recruited with extended extinction training or after administration of a partial agonist, both of which lead to effective extinction retention.

Deficits in opioid receptor-mediated prediction error contribute to impaired fear extinction during adolescence.

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/J.BRAT.2020.103713

The impact of obesity and hypercaloric diet consumption on anxiety and emotional behavior across the lifespan

Publisher: Elsevier BV

Date: 12-2017

DOI: 10.1016/J.NEUBIOREV.2017.10.014

Abstract: Obesity is an increasing problem in young people. Childhood obesity and overweight have increased rapidly on a global scale, and have tripled in the past 30 years, to affect approximately one in five children. Diets high in refined fats and sugar are a major contributor to the development of obesity, and the effects of such obesity-inducing hypercaloric diets on brain function may contribute to the high prevalence of anxiety disorders in people with obesity. Anxiety disorders typically emerge in childhood and adolescence, and symptoms often continue into adulthood. Based on this symptomology, we consider anxiety-related behavioral consequences of hypercaloric diets across development. We review research on the effects of hypercaloric dietary manipulations across the lifespan on emotion regulation and the neurobiological mechanisms that underpin these processes. Cumulatively, the findings reveal that gestation and the juvenile/adolescent developmental periods may be early-life windows of vulnerability for developing anxiety in later life due to the augmented effects of these diets on neuroendocrine stress systems and the maturation of neural circuitry supporting emotion regulation.

Inhibition of mGluR1 and IP3Rs impairs long-term memory formation in young chicks.

Publisher: Elsevier BV

Date: 07-2008

DOI: 10.1016/J.NLM.2008.04.004

Abstract: Calcium (Ca(2+)) is involved in a myriad of cellular functions in the brain including synaptic plasticity. However, the role of intracellular Ca(2+) stores in memory processing remains poorly defined. The current study explored a role for glutamate-dependent intracellular Ca(2+) release in memory processing via blockade of metabotropic glutamate receptor subtype 1 (mGluR1) and inositol (1,4,5)-trisphosphate receptors (IP(3)Rs). Using a single-trial discrimination avoidance task developed for the young chick, administration of the specific and potent mGluR1 antagonist JNJ16259685 (500nM, immediately post-training, ic), or the IP(3)R antagonist Xestospongin C (5microM, immediately post-training, ic), impaired retention from 90min post-training. These findings are consistent with mGluR1 activating IP(3)Rs to release intracellular Ca(2+) required for long-term memory formation and have been interpreted within an LTP2 model. The consequences of different patterns of retention loss following ryanodine receptor (RyR) and IP(3)R inhibition are discussed.

Developmental changes in functional connectivity between the prefrontal cortex and amygdala following fear extinction

Publisher: Elsevier BV

Date: 11-2023

DOI: 10.1016/J.NLM.2023.107847

Esketamine as a treatment for paediatric depression: questions of safety and efficacy.

Publisher: Elsevier BV

Date: 10-2020

DOI: 10.1016/S2215-0366(19)30521-8

Impaired fear extinction in adolescent rodents: Behavioural and neural analyses

Publisher: Elsevier BV

Date: 11-2016

DOI: 10.1016/J.NEUBIOREV.2016.05.019

Abstract: Despite adolescence being a developmental window of vulnerability, up until very recently there were surprisingly few studies on fear extinction during this period. Here we summarise the recent work in this area, focusing on the unique behavioural and neural characteristics of fear extinction in adolescent rodents, and humans where relevant. A prominent hypothesis posits that anxiety disorders peak during late childhood/adolescence due to the non-linear maturation of the fear inhibition neural circuitry. We discuss evidence that impaired extinction retention in adolescence is due to subregions of the medial prefrontal cortex and amygdala mediating fear inhibition being underactive while other subregions that mediate fear expression are overactive. We also review work on various interventions and surprising circumstances which enhance fear extinction in adolescence. This latter work revealed that the neural correlates of extinction in adolescence are different to that in younger and older animals even when extinction retention is not impaired. This growing body of work highlights that adolescence is a unique period of development for fear inhibition.

Maturational Changes in Prefrontal and Amygdala Circuits in Adolescence: Implications for Understanding Fear Inhibition during a Vulnerable Period of Development

Publisher: MDPI AG

Date: 18-03-2019

DOI: 10.3390/BRAINSCI9030065

Abstract: Anxiety disorders that develop in adolescence represent a significant burden and are particularly challenging to treat, due in no small part to the high occurrence of relapse in this age group following exposure therapy. This pattern of persistent fear is preserved across species relative to those younger and older, adolescents consistently show poorer extinction, a key process underpinning exposure therapy. This suggests that the neural processes underlying fear extinction are temporarily but profoundly compromised during adolescence. The formation, retrieval, and modification of fear- and extinction-associated memories are regulated by a forebrain network consisting of the prefrontal cortex (PFC), the amygdala, and the hippoc us. These regions undergo robust maturational changes in early life, with unique alterations in structure and function occurring throughout adolescence. In this review, we focus primarily on two of these regions—the PFC and the amygdala—and discuss how changes in plasticity, synaptic transmission, inhibition/excitation, and connectivity (including modulation by hippoc al afferents to the PFC) may contribute to transient deficits in extinction retention. We end with a brief consideration of how exposure to stress during this adolescent window of vulnerability can permanently disrupt neurodevelopment, leading to lasting impairments in pathways of emotional regulation.

Relearning a context-shock association after forgetting is an NMDAr-independent process.

Publisher: Elsevier BV

Date: 09-2015

DOI: 10.1016/J.PHYSBEH.2014.11.004

Abstract: Infantile amnesia (i.e., the rapid rate of forgetting in young animals) is at least partially due to a memory retrieval, rather than a storage, failure as studies have shown that these engrams can continue to influence later behavior. For ex le, prior conditioning affects the neural mechanisms underlying future learning. In adult animals, the initial learning of a context-shock association depends upon N-Methyl-D-Aspartate (NMDA) receptors, but this conditioning renders subsequent learning to a similar context NMDAr-independent. In the present study, we examined whether this transition from NMDAr-dependent to NMDAr-independent context conditioning occurs even after infantile amnesia. Experiment 1 demonstrated that infant (i.e., postnatal day 17) rats acquire a context-shock association when trained with multiple shocks, as assessed by context freezing one day later. However, they exhibit significant forgetting of this association 10days later. Experiments 2 and 3 showed that even when animals had forgotten the initial learning experience, future conditioning to the same context was NMDAr-independent. There was evidence of a transition to NMDAr-independent context fear learning in animals exposed only to the foot shock in infancy (Experiment 3) or only to the context in infancy (Experiment 3 but not Experiment 2). These latter results suggest that animals do not have to be exposed to the entire conditioning procedure at postnatal day 17 to show a transition to NMDAr-independent context learning. These experiments add to a growing body of evidence that forgotten infant memories can continue to affect later behavior by demonstrating that prior experience alters the mechanisms of future learning.

The interaction of REM sleep with safety learning in humans: could a good night's sleep alter a traumatic experience?

Publisher: Society for Neuroscience

Date: 28-01-2015

DOI: 10.1523/JNEUROSCI.4370-14.2015

Real-World Intake of Dietary Sugars Is Associated with Reduced Cortisol Reactivity Following an Acute Physiological Stressor

Publisher: MDPI AG

Date: 2023

DOI: 10.3390/NU15010209

Abstract: There is increasing academic and clinical interest in understanding the nature of the relation between diet and response to stress exposure as a risk factor for mental illness. Cross-species evidence shows that conditions of chronic and acute stress increase the intake of, and preference for, caloric-dense palatable foods, a phenomenon thought to be explained by the mitigating effects of comfort foods on the activity of the stress-response network. It is largely unknown whether and how real-world dietary intake of saturated fat and sugars impacts stress responsivity in humans. Therefore, here we examined whether real-world dietary intake of saturated fat and sugars predicted salivary cortisol reactivity following an acute physiological stressor. Multilevel modelling of four salivary cortisol measures collected up to 65 min after the stressor on 54 participants (18–49 years old) were analyzed using a quadratic growth curve model. Sugar intake significantly predicted a weaker cortisol response following the Cold Pressor Test (CPT) controlling for BMI and gender, revealing an inhibitory effect of caloric-dense diets on cortisol reactivity to stress. As the consumption of sugar rose in iduals had lower post-stressor cortisol levels, a smaller rate of increase in cortisol 20 and 35 min after the CPT, a lower cortisol peak, and an overall weaker quadratic effect. These observations add to a growing body of evidence reporting suppressive effects of high-energy foods on stress-associated glucocorticoids reactivity and are consistent with the comfort food hypothesis, where people are seen as motivated to eat palatable foods to alleviate the detrimental repercussions of stressor exposure.

Memory retrieval before or after extinction reduces recovery of fear in adolescent rats

Publisher: Cold Spring Harbor Laboratory

Date: 15-08-2013

DOI: 10.1101/LM.031989.113

Abstract: Adolescent rats exhibit impaired extinction retention compared to pre-adolescent and adult rats. A single nonreinforced exposure to the conditioned stimulus (CS a retrieval trial) given shortly before extinction has been shown in some circumstances to reduce the recovery of fear after extinction in adult animals. This study investigated whether a retrieval–extinction procedure would reduce the recovery of extinguished fear in adolescent rats. Furthermore, the effect of the retrieval–extinction sequence on fear recovery was examined by presenting the retrieval trial following extinction to some animals. In Experiment 1 adolescent rats received one nonreinforced CS presentation (a retrieval trial) or equivalent context exposure (no retrieval) 10 min before fear extinction. A retrieval trial shortly before extinction reduced overall levels of fear in both test contexts (i.e., it improved extinction retention and reduced renewal). In Experiment 2 a weakening of renewal was observed with a retrieval–extinction manipulation, regardless of whether the retrieval trial occurred in the training or extinction context. A key result was that a retrieval trial 10 min, but not 6 h, after extinction led to reduced overall levels of fear similar to that observed if the retrieval trial was given before extinction (Experiments 3 and 4), inconsistent with the current interpretation of the reduction in relapse being due to a disruption of reconsolidation. Together, these findings show that the impaired extinction retention observed in adolescents can be ameliorated by a very simple behavioral manipulation, but also raise some questions about the mechanisms underlying the retrieval–extinction effect.

Differences in the persistence of spatial memory deficits induced by a chronic stressor in adolescents compared to juveniles.

Publisher: Wiley

Date: 25-06-2018

DOI: 10.1002/DEV.21750

Abstract: Adolescence is thought of as a stress-sensitive developmental period. While many studies have compared adolescent responses to stress relative to that of adults, a growing body of work has examined stress responses in juveniles. Here we investigated if a chronic stressor has a differential effect on spatial memory in rats depending on whether it occurs during adolescence or the juvenile period. Male rats were exposed to the stress hormone corticosterone (Cort) in their drinking water, a vehicle control (2.5% ethanol), or water, for 7 days before being tested on a novel Object/Place task 6 days or 6 weeks later. Exposure to Cort or ethanol at either age impaired spatial memory at the 6-day test. The ethanol induced impairment was attenuated 6 weeks later. However, rats given Cort during adolescence, but not the juvenile period, were still impaired. Together, these results suggest that adolescence is indeed a stress-sensitive period.

Impaired fear extinction retention and increased anxiety-like behaviours induced by limited daily access to a high-fat/high-sugar diet in male rats: Implications for diet-induced prefrontal cortex dysregulation

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.NLM.2016.10.002

Abstract: Anxiety disorders and obesity are both common in youth and young adults. Despite increasing evidence that over-consumption of palatable high-fat/high-sugar "junk" foods leads to adverse neurocognitive outcomes, little is known about the effects of palatable diets on emotional memories and fear regulation. In the present experiments we examined the effects of daily 2h consumption of a high-fat/high-sugar (HFHS) food across adolescence on fear inhibition and anxiety-like behaviour in young adult rats. Rats exposed to the HFHS diet exhibited impaired retention of fear extinction and increased anxiety-like behaviour in an emergence test compared to rats fed a standard diet. The HFHS-fed rats displayed diet-induced changes in prefrontal cortex (PFC) function which were detected by altered expression of GABAergic parvalbumin-expressing inhibitory interneurons and the stable transcription factor ΔFosB which accumulates in the PFC in response to chronic stimuli. Immunohistochemical analyses of the medial PFC revealed that animals fed the HFHS diet had fewer parvalbumin-expressing cells and increased levels of FosB/ΔFosB expression in the infralimbic cortex, a region implicated in the consolidation of fear extinction. There was a trend towards increased IBA-1 immunoreactivity, a marker of microglial activation, in the infralimbic cortex after HFHS diet exposure but expression of the extracellular glycoprotein reelin was unaffected. These findings demonstrate that a HFHS diet during adolescence is associated with reductions of prefrontal parvalbumin neurons and impaired fear inhibition in adulthood. Adverse effects of HFHS diets on the mechanisms of fear regulation may precipitate a vulnerability in obese in iduals to the development of anxiety disorders.

D-Cycloserine facilitates fear extinction in adolescent rats and differentially affects medial and lateral prefrontal cortex activation

Publisher: Elsevier BV

Date: 08-2018

DOI: 10.1016/J.PNPBP.2018.06.007

Abstract: Adolescent humans and rodents are impaired in extinguishing learned fear relative to younger and older groups. This impairment could be due to differences in recruitment of medial prefrontal cortex (PFC), orbitofrontal cortex (OFC), or amygdala during extinction. For ex le, unlike juveniles and adults, adolescent rats do not express extinction-induced increases in phosphorylated mitogen activated protein kinase (pMAPK), a marker of synaptic plasticity, in the medial PFC. The NMDA receptor partial agonist d-cycloserine (DCS) improves extinction retention in adolescent rats. We investigated whether DCS affected recruitment of the PFC and amygdala during extinction by measuring pMAPK-immunoreactive (IR) neurons. Adolescent rats were trained to fear a conditioned stimulus in one context followed by extinction in a second context or equivalent context exposure only (i.e., no extinction). DCS (15 mg/kg, s.c.) or saline was administered systemically immediately after extinction training or context exposure. DCS enhanced extinction learning and this was associated with increased activation of the MAPK signaling pathway in the OFC after extinction training and increased activation in the medial PFC and amygdala at extinction retention. These findings suggest that DCS improves extinction learning in adolescents because it augments OFC contributions to extinction learning, enabling better medial prefrontal contributions to extinction retention.

Forming competing fear learning and extinction memories in adolescence makes fear difficult to inhibit.

Publisher: Cold Spring Harbor Laboratory

Date: 15-10-2015

DOI: 10.1101/LM.039487.114

Abstract: Fear inhibition is markedly impaired in adolescent rodents and humans. The present experiments investigated whether this impairment is critically determined by the animal's age at the time of fear learning or their age at fear extinction. Male rats ( n = 170) were tested for extinction retention after conditioning and extinction at different ages. We examined neural correlates of impaired extinction retention by detection of phosphorylated mitogen-activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions. Unexpectedly, adolescent rats exhibited good extinction retention if fear was acquired before adolescence. Further, fear acquired in adolescence could be successfully extinguished in adulthood but not within adolescence. Adolescent rats did not show extinction-induced increases in pMAPK-IR in the medial prefrontal cortex or the basolateral amygdala, or a pattern of reduced caudal central amygdala pMAPK-IR, as was observed in juveniles. This d ened prefrontal and basolateral amygdala MAPK activation following extinction in adolescence occurred even when there was no impairment in extinction retention. In contrast, only adolescent animals that exhibited impaired extinction retention showed elevated pMAPK-IR in the posterior paraventricular thalamus. These data suggest that neither the animal's age at the time of fear acquisition or extinction determines whether impaired extinction retention is exhibited. Rather, it appears that forming competing fear conditioning and extinction memories in adolescence renders this a vulnerable developmental period in which fear is difficult to inhibit. Furthermore, even under conditions that promote good extinction, the neural correlates of extinction in adolescence are different than those recruited in animals of other ages.

Fear extinction learning and retention during adolescence in rats and mice: A systematic review

Publisher: Elsevier BV

Date: 12-2021

DOI: 10.1016/J.NEUBIOREV.2021.10.044

The role of intracellular calcium stores in synaptic plasticity and memory consolidation.

Publisher: Elsevier BV

Date: 08-2013

DOI: 10.1016/J.NEUBIOREV.2013.04.011

Abstract: Memory processing requires tightly controlled signalling cascades, many of which are dependent upon intracellular calcium (Ca(2+)). Despite this, most work investigating calcium signalling in memory formation has focused on plasma membrane channels and extracellular sources of Ca(2+). The intracellular Ca(2+) release channels, ryanodine receptors (RyRs) and inositol (1,4,5)-trisphosphate receptors (IP3Rs) have a significant capacity to regulate intracellular Ca(2+) signalling. Evidence at both cellular and behavioural levels implicates both RyRs and IP3Rs in synaptic plasticity and memory formation. Pharmacobehavioural experiments using young chicks trained on a single-trial discrimination avoidance task have been particularly useful by demonstrating that RyRs and IP3Rs have distinct roles in memory formation. RyR-dependent Ca(2+) release appears to aid the consolidation of labile memory into a persistent long-term memory trace. In contrast, IP3Rs are required during long-term memory. This review discusses various functions for RyRs and IP3Rs in memory processing, including neuro- and glio-transmitter release, dendritic spine remodelling, facilitating vasodilation, and the regulation of gene transcription and dendritic excitability. Altered Ca(2+) release from intracellular stores also has significant implications for neurodegenerative conditions.

Blocking SK channels impairs long-term memory formation in young chicks

Publisher: Elsevier BV

Date: 2011

DOI: 10.1016/J.BBR.2010.07.032

Abstract: The role of small-conductance calcium-activated potassium (SK) channels in memory formation was explored in chicks trained on a single-trial discrimination avoidance task. Blockade of SK channels using apamin (1 nM, 0.02 ng/hem, i.c.) impaired long-term memory retention when administered between 10 min prior to, and 30 min after, training. Apamin (1 nM, 0.02 ng/hem, immediately post-training, i.c.) resulted in persistent impairment of retention during the long-term memory stage by 90 min post-training until at least 24 h post-training, indicating SK channels contribute to long-term memory.

Pharmacobehavioural Evidence for Nitric Oxide and Noradrenaline Interactions With Ryanodine Receptors During Memory Formation in the Young Chick

Publisher: American Psychological Association (APA)

Date: 2011

DOI: 10.1037/A0022537

Abstract: Impairment of nitric oxide (NO) production, ryanodine receptor (RyR) calcium channel function and adrenoceptor activation have been found to prevent the formation of the long-term memory stage in young chicks trained on a single-trial discrimination avoidance task. The current study investigated whether these three activities were linked, and if so, the sequence of activation. Young chicks were trained using either a strongly or weakly reinforced variant of the single-trial discrimination avoidance task, yielding either a persistent or labile memory trace, respectively. Following strongly reinforced training, retention loss induced by a RyR inhibitor was prevented by a NO donor or noradrenaline (NA). A RyR agonist also prevented retention loss induced by either NO synthase or β1+2-adrenoceptor inhibition. These findings were interpreted to reflect the capacity of NO, RyR-dependent calcium release and NA to modulate memory by preventing retention loss. A second set of studies used weakly reinforced training. Although the administration of a RyR agonist promoted long-term memory formation, this facilitation was compromised in the presence of a β1+2-adrenoceptor antagonist, but not a NO synthase inhibitor. Similarly, the inhibition of RyRs interfered with the facilitation of retention induced by a NO donor, but not NA. These differential findings with weakly reinforced training suggest that NO facilitates memory formation through mechanisms involving RyR-dependent calcium release. The findings also indicate that RyRs may promote memory formation through noradrenergic activation of β2-adrenoceptors. This study demonstrates an intricate role for RyRs underlying memory formation.

Developmental differences in the effects of CB1/2R agonist WIN55212-2 on extinction of learned fear.

Publisher: Elsevier BV

Date: 04-2019

DOI: 10.1016/J.PNPBP.2019.109834

Abstract: Adolescence is characterised by substantial changes in emotion regulation and, in particular, impaired extinction consolidation and retention. In this study, we replicated the well-established finding that increasing the activation of cannabinoid receptor 1 (CB1R) via the agonist WIN55212-2 improves fear extinction in adult rodents before examining whether this adjunct would also rescue the extinction retention deficit seen in adolescent rodents. Contrary to the effects in adults, we found that WIN55212-2 impaired within-session acquisition of extinction in adolescent rats with no effect on extinction retention. The same effects of WIN55212-2 were observed for juvenile rats, and did not vary as a function of drug dose. Increased fear expression observed during extinction training was not a result of altered locomotor or anxiety-like behaviour in adolescent rats, as assessed by the open field test. Lastly, we observed a linear decrease in CB1R protein expression across age (i.e., from juveniles, to adolescents, and adults) in both the medial prefrontal cortex and amygdala, two regions implicated in fear expression and extinction, suggesting that there is continued refinement of the endocannabinoid system across development in two regions involved in extinction. Our findings suggest that the expression and extinction of fear in developing rats is differentially affected by CB1R agonism due to an immature endocannabinoid system.

D-cycloserine does not facilitate fear extinction by reducing conditioned stimulus processing or promoting conditioned inhibition to contextual cues

Publisher: Cold Spring Harbor Laboratory

Date: 14-09-2012

DOI: 10.1101/LM.026674.112

Abstract: The NMDA receptor partial agonist d -cycloserine (DCS) enhances the extinction of learned fear in rats and exposure therapy in humans with anxiety disorders. Despite these benefits, little is known about the mechanisms by which DCS promotes the loss of fear. The present study examined whether DCS augments extinction retention (1) through reductions in conditioned stimulus (CS) processing or (2) by promoting the development of conditioned inhibition to contextual cues. Rats administered DCS prior to extinction showed enhanced long-term extinction retention (Experiments 3 and 4). The same nonreinforced CS procedure used in extinction also reduced freezing at test when presented as pre-exposure before conditioning, demonstrating latent inhibition (Experiment 1). DCS administered shortly prior to pre-exposure had no effect on latent inhibition using parameters which produced weak (Experiment 2) or strong (Experiment 3) expression of latent inhibition. Therefore, DCS facilitated learning involving CS-alone exposures, but only when these exposures occurred after (extinction) and not before (latent inhibition) conditioning. We also used a retardation test procedure to examine whether the extinction context gained inhibitory properties for rats given DCS prior to extinction. With three different footshock intensities, there was no evidence that DCS promoted accrual of associative inhibition to the extinction context (Experiment 4). The present findings demonstrate that DCS does not facilitate extinction by reducing CS processing or causing the extinction context to become a conditioned inhibitor. Investigations into the mechanisms underlying the augmentation of extinction by DCS are valuable for understanding how fear can be inhibited.

Pharmacological Enhancement of Extinction Retention in Non-stressed Adolescent Rats but Not Those Exposed to Chronic Corticosterone

Publisher: Frontiers Media SA

Date: 16-03-2022

DOI: 10.3389/FNINS.2022.822709

Abstract: In iduals exposed to chronic adverse experiences in childhood and adolescence are at increased risk of developing neuropsychiatric illnesses such as mood and anxiety disorders. Symptoms of anxiety disorders can often be reduced through exposure therapy, which is based on the process of extinction. Although chronic stress in adolescence is known to exacerbate the impaired extinction of learned fear during this period of development, it remains unclear whether exposure to stressors in adolescence qualitatively affects the mechanisms underlying fear extinction. Brain-derived neurotrophic factor (BDNF) and its principle receptor, tropomyosin receptor kinase B (TrkB), are involved in neuroplasticity underlying fear extinction. The small-molecule TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) improves fear extinction and reduces fear relapse (reinstatement) in adult mice when administered prior to extinction training but its effects in younger ages are unknown. In this study we tested whether 7,8-DHF enhances extinction retention and leads to less renewal in both stressed and non-stressed adolescent rats. Pre-extinction injection of 7,8-DHF led to lower levels of CS-elicited freezing in both the extinction and conditioning contexts in non-stressed adolescent male rats, but not in those given 7 days of corticosterone. These findings indicate that chronic stress interferes with the effectiveness of pharmacological agonism of TrkB in enhancing fear extinction in adolescence. A greater understanding of the mechanisms underlying extinction in adolescence and the effect of chronic corticosterone exposure on those mechanisms may inform a deeper understanding of the etiology and treatment of pediatric stress-related disorders.

La Trobe University

Location: Australia

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Monash University

Location: Australia

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UNSW Sydney

Location: Australia

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La Trobe University

Location: No location found

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Discovery Early Career Researcher Award - Grant ID: DE170100392

Start Date: 05-2017

End Date: 12-2021

Amount: $340,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP230103116

Start Date: 07-2023

End Date: 06-2026

Amount: $360,000.00

Funder: Australian Research Council

Discovery Projects - Grant ID: DP220103309

Start Date: 04-2022

End Date: 12-2025

Amount: $359,699.00

Funder: Australian Research Council