ORCID Profile
0000-0002-1299-4300
Current Organisation
Deakin University
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Psychology | Biological Psychology (Neuropsychology, Psychopharmacology, Physiological Psychology) | Central Nervous System | Neurocognitive Patterns and Neural Networks | Biological psychology | Learning motivation and emotion | Behavioural neuroscience | Memory Structures | Developmental Psychology and Ageing
ANZSRC Socio-Economic Objective (SEO)
Mental Health | Expanding Knowledge in the Biological Sciences | Expanding Knowledge in Psychology and Cognitive Sciences | Nervous System and Disorders | Expanding Knowledge in the Medical and Health Sciences |
Related Links
Publications
A developmental dissociation of context and GABA effects on extinguished fear in rats.
Publisher: American Psychological Association (APA)
Date: 2007
DOI: 10.1037/0735-7044.121.1.131
Abstract: Although extinction has attracted considerable attention in recent years, there has been very little empirical work on extinction during development. Using Pavlovian fear conditioning, the authors provide evidence for developmental differences in extinction. Specifically, Postnatal Day (PND) 23 rats exhibited recovery of an extinguished freezing response to an auditory conditioned stimulus when tested in a context different from that in which extinction occurred (i.e., renewal) or when injected with the gamma-amino butyric acid (GABA) inverse agonist FG7142 prior to test. In contrast, PND 16 rats failed to exhibit either of these effects, although a subsequent experiment demonstrated that FG7142 alleviated spontaneous forgetting in PND 16 rats. Taken together, it appears that there are fundamental differences in the processes involved in extinction across development.
Transcriptional Modulation of the Hippo Signaling Pathway by Drugs Used to Treat Bipolar Disorder and Schizophrenia
Publisher: MDPI AG
Date: 02-07-2021
DOI: 10.3390/IJMS22137164
Abstract: Recent reports suggest a link between positive regulation of the Hippo pathway with bipolar disorder (BD), and the Hippo pathway is known to interact with multiple other signaling pathways previously associated with BD and other psychiatric disorders. In this study, neuronal-like NT2 cells were treated with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM), or vehicle control for 24 h. Genome-wide mRNA expression was quantified and analyzed using gene set enrichment analysis (GSEA), with genes belonging to Hippo, Wnt, Notch, TGF- β, and Hedgehog retrieved from the KEGG database. Five of the eight drugs downregulated the genes of the Hippo pathway and modulated several genes involved in the interacting pathways. We speculate that the regulation of these genes, especially by aripiprazole, clozapine, and quetiapine, results in a reduction of MAPK and NFκB pro-inflammatory signaling through modulation of Hippo, Wnt, and TGF-β pathways. We also employed connectivity map analysis to identify compounds that act on these pathways in a similar manner to the known psychiatric drugs. Thirty-six compounds were identified. The presence of antidepressants and antipsychotics validates our approach and reveals possible new targets for drug repurposing.
The Metabotropic Glutamate 5 Receptor Modulates Extinction and Reinstatement of Methamphetamine-Seeking in Mice
Publisher: Public Library of Science (PLoS)
Date: 04-07-2013
Sex differences in the neurochemistry of frontal cortex: Impact of early life stress
Publisher: Wiley
Date: 27-10-2021
DOI: 10.1111/JNC.15208
The metabotropic glutamate 5 receptor is necessary for extinction of cocaine-associated cues
Publisher: Wiley
Date: 18-02-2016
DOI: 10.1111/BPH.13437
mGlu5: A double-edged sword for aversive learning related therapeutics
Publisher: Portico
Date: 18-01-2021
Extinction and drug‐induced reinstatement of cocaine seeking following self‐administration or conditioned place preference in adolescent and adult rats
Publisher: Wiley
Date: 15-07-2021
DOI: 10.1002/DEV.22017
Abstract: Adolescence marks a particularly vulnerable period to developing substance use disorders, and people who start using drugs in adolescence are more likely to relapse. A limited number of studies have investigated age difference in relapse following re-exposure to the drug after a period of abstinence. Using a cocaine self-administration paradigm, we showed no age difference in acquisition or extinction of self-administration. Interestingly, adolescent rats displayed impaired cocaine-primed reinstatement of cocaine seeking. Using the same dose as that self-administered in the first experiment, we then investigated age differences in acquisition and extinction of conditioned place preference, as well as locomotor sensitization. While there were no differences in locomotor activity or acquisition of preference, adolescents failed to extinguish their preference, even when the number of extinction sessions was doubled from what adults received. Taken together, these results suggest that while cocaine has similar rewarding and reinforcing effects regardless of age, adolescents may attribute stronger salience to the drug-associated context. In addition, re-exposure to cocaine itself may not be a strong relapse trigger in adolescence. Overall, these findings suggest that we should focus more on alleviating drug-context salience compared to re-exposure to substance in order to reduce relapse of drug seeking in adolescents.
Exercise alters mouse sperm small noncoding RNAs and induces a transgenerational modification of male offspring conditioned fear and anxiety
Publisher: Springer Science and Business Media LLC
Date: 02-05-2017
DOI: 10.1038/TP.2017.82
Abstract: There is growing evidence that the preconceptual lifestyle and other environmental exposures of a father can significantly alter the physiological and behavioral phenotypes of their children. We and others have shown that paternal preconception stress, regardless of whether the stress was experienced during early-life or adulthood, results in offspring with altered anxiety and depression-related behaviors, attributed to hypothalamic–pituitary–adrenal axis dysregulation. The transgenerational response to paternal preconceptual stress is believed to be mediated by sperm-borne small noncoding RNAs, specifically microRNAs. As physical activity confers physical and mental health benefits for the in idual, we used a model of voluntary wheel-running and investigated the transgenerational response to paternal exercise. We found that male offspring of runners had suppressed reinstatement of juvenile fear memory, and reduced anxiety in the light–dark apparatus during adulthood. No changes in these affective behaviors were observed in female offspring. We were surprised to find that running had a limited impact on sperm-borne microRNAs. The levels of three unique microRNAs (miR-19b, miR-455 and miR-133a) were found to be altered in the sperm of runners. In addition, we discovered that the levels of two species of tRNA-derived RNAs (tDRs)—tRNA-Gly and tRNA-Pro—were also altered by running. Taken together, we believe this is the first evidence that paternal exercise is associated with an anxiolytic behavioral phenotype of male offspring and altered levels of small noncoding RNAs in sperm. These small noncoding RNAs are known to have an impact on post-transcriptional gene regulation and can thus change the developmental trajectory of offspring brains and associated affective behaviors.
Divergent prefrontal dopaminergic mechanisms mediate drug- and fear-associated cue extinction during adolescence versus adulthood
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.EURONEURO.2017.11.004
Abstract: Cue-associated learning is vital to guiding behaviour for survival. Adolescence represents a key developmental stage for perturbations in cue-related learning, including a characteristic deficit in cue extinction learning. The present review summarizes evidence from animal and human literature that cue extinction is critically mediated by prefrontal dopamine, a system that undergoes dramatic reorganization during adolescence. We propose that extinction learning and memory is governed by a developmentally dynamic balance of dopamine receptors in the prefrontal cortex, which changes across adolescence into adulthood. This is contrary to the previous idea that extinction deficits during adolescence reflect inefficiency in the same neural circuitry as adults. This leads to proposal of the novel theory that cue extinction involves ergent prefrontal dopaminergic mechanisms depending on the age of extinction.
A dissociation between renewal and contextual fear conditioning in juvenile rats
Publisher: Wiley
Date: 06-04-2017
DOI: 10.1002/DEV.21516
Abstract: We investigated whether juvenile rats do not express renewal following extinction of conditioned fear due to their inability to form a long-term contextual fear memory. In experiment 1, postnatal day (P) 18 and 25 rats received 3 white-noise and footshock pairings, followed by 60 white-noise alone presentations the next day. When tested in a different context to extinction, P25 rats displayed renewal whereas P18 rats did not. Experiments 2A and 2B surprisingly showed that P18 and P25 rats do not show differences in contextual and cued fear, regardless of the conditioning-test intervals and the number of white-noise-footshock pairings received. Finally, we observed age differences in contextual fear when P25 rats were weaned at P21 in experiment 3. These results indicate that the developmental dissociation observed in renewal of extinguished fear is not related to the widely believed late emergence of contextual fear learning.
Age of Onset and Its Related Factors in Cocaine or Methamphetamine Use in Adults from the United States: Results from NHANES 2005–2018
Publisher: MDPI AG
Date: 22-11-2021
Abstract: Cocaine and meth hetamine are widely used illicit psychostimulants worldwide, with steadily increasing global markets that may impact on the frequency of use. Importantly, their use typically begins in youth. This is a particular concern because there is a link between the early age of first substance use and severity of substance use disorder later in life. The aim of the present study was therefore to investigate trends in prevalence, frequency, and age of onset of cocaine or meth hetamine use between 2005 and 2018 in the United States, using the nationally representative NHANES datasets. Factors associated with the ages of cocaine or meth hetamine use onset were also identified. From 2005 to 2018, prevalence and frequencies of cocaine or meth hetamine use increased, while age of onset remained relatively stable (~20 years of age). Annual household income, use of other substances, and intravenous drug use were identified as factors associated with early onset cocaine or meth hetamine use. These factors have important implications toward developing new prevention programs to reduce psychostimulant use.
Extinction of conditioned cues attenuates incubation of cocaine craving in adolescent and adult rats.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.NLM.2016.09.002
Abstract: Relapse to drug use is often precipitated by exposure to drug associated cues that evoke craving. Cue-induced drug craving has been observed in both animals and humans to increase over the first few weeks of abstinence and remain high over extended periods, a phenomenon known as 'incubation of craving'. As adolescence represents a period of vulnerability to developing drug addiction, potentially due to persistent reactivity to drug associated cues, we first compared incubation of cocaine craving in adolescent and adult rats. Adolescent (P35) and adult (P70) rats were trained to lever press to obtain intravenous cocaine, with each drug delivery accompanied by a light cue that served as the conditioned stimulus (CS). Following acquisition of stable responding, rats were tested for cue-induced cocaine-seeking after either 1 or 30days of abstinence. Additional groups of rats were also tested after 30days of abstinence, however these rats were subjected to a cue extinction session 1week into the abstinence period. Rats were injected with aripiprazole, a dopamine 2 receptor (D2R)-like partial agonist, or vehicle, 30min prior to cue extinction. We found that adolescent and adult rats acquired and maintained a similar level of cocaine self-administration, and rats of both ages exhibited a higher level of cue-induced cocaine-seeking if they were tested after 30days of abstinence compared to 1day. Incubation of cocaine craving was significantly reduced to 1day levels in both adults and adolescents that received cue extinction training. Administration of aripiprazole prior to cue extinction did not further reduce cue-induced drug-seeking. These results indicate that cue extinction training during abstinence may effectively reduce cue-induced relapse at a time when cue-induced drug craving is usually high.
Genetics of methamphetamine use disorder: A systematic review and meta-analyses of gene association studies.
Publisher: Elsevier BV
Date: 2021
Orexin-1 receptor signalling in the prelimbic cortex and ventral tegmental area regulates cue-induced reinstatement of ethanol-seeking in iP rats
Publisher: Wiley
Date: 20-04-2015
DOI: 10.1111/ADB.12251
Abstract: Orexins (hypocretins) are hypothalamic neuropeptides that innervate the entire neuraxis, including the prelimbic cortex and ventral tegmental area and have been implicated in ethanol-seeking behaviour. The present study aimed to use the orexin-1 (OX1 ) receptor antagonist SB-334867 to examine the role of prelimbic cortex and ventral tegmental area OX1 receptors in cue-induced reinstatement of ethanol-seeking. Ethanol-preferring rats (iP) rats were trained to self-administer ethanol (10 percent v/v, FR3) or sucrose (0.2-1 percent w/v, FR3) in the presence of reward-associated cues before being implanted with indwelling guide cannulae. Rats then underwent extinction training for 11 days. On test days, rats were given a microinjection of vehicle or SB-334867 (3 μg/side) and presented with reward-associated cues to precipitate reinstatement. Results show SB-334867 infused into the prelimbic cortex attenuated cue-induced reinstatement of ethanol-seeking, but not sucrose-seeking. OX1 antagonism in the ventral tegmental area also attenuated cue-induced reinstatement of ethanol-seeking. These findings suggest that OX1 receptors located in the prelimbic cortex and ventral tegmental area are part of a circuit driving cue-mediated ethanol-seeking behaviour.
Postnatal development of neurotransmitter systems and their relevance to extinction of conditioned fear
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.NLM.2016.10.018
Abstract: Remembering and forgetting are fundamental features of an organism. Extinction is a type of forgetting where there is a decrease in the significance and/or the meaning of an associative memory when elements of that memory no longer predict one another. The neural mechanisms underlying extinction of fear memories have been extensively studied in the laboratory because extinction processes are clinically relevant to exposure therapies that treat anxiety disorders. However, only in the last decade have we begun to unveil the similarities and differences in plasticity underlying extinction across development. So far it is clear that extinction is a developmentally dissociated process in behavior and in pharmacology, however there are many large gaps in the literature in understanding how the developmental trajectory of different neurotransmitters contribute to changes in the nature of extinction across development. We attempt to address these gaps in the present review. Major neurotransmitter systems including the glutamatergic and GABAergic systems, the monoamines, the endogenous opioid and cannabinoid systems, acetylcholines, and neuropeptides such as oxytocin have all been identified to play some role in extinction of fear memories and have been covered in this review. We hope to facilitate more research into mechanisms of extinction at different stages of life, especially noting that mental disorders are increasingly classified as neurodevelopmental disorders.
Cocaine-Induced Changes in Tonic Dopamine Concentrations Measured Using Multiple-Cyclic Square Wave Voltammetry in vivo
Publisher: Frontiers Media SA
Date: 06-07-2021
DOI: 10.3389/FPHAR.2021.705254
Abstract: For over 40 years, in vivo microdialysis techniques have been at the forefront in measuring the effects of illicit substances on brain tonic extracellular levels of dopamine that underlie many aspects of drug addiction. However, the size of microdialysis probes and s ling rate may limit this technique’s ability to provide an accurate assessment of drug effects in microneural environments. A novel electrochemical method known as multiple-cyclic square wave voltammetry (M-CSWV), was recently developed to measure second-to-second changes in tonic dopamine levels at microelectrodes, providing spatiotemporal resolution superior to microdialysis. Here, we utilized M-CSWV and fast-scan cyclic voltammetry (FSCV) to measure changes in tonic or phasic dopamine release in the nucleus accumbens core (NAcc) after acute cocaine administration. Carbon-fiber microelectrodes (CFM) and stimulating electrodes were implanted into the NAcc and medial forebrain bundle (MFB) of urethane anesthetized (1.5 g/kg i.p.) Sprague-Dawley rats, respectively. Using FSCV, depths of each electrode were optimized by determining maximal MFB electrical stimulation-evoked phasic dopamine release. Changes in phasic responses were measured after a single dose of intravenous saline or cocaine hydrochloride (3 mg/kg n = 4). In a separate group, changes in tonic dopamine levels were measured using M-CSWV after intravenous saline and after cocaine hydrochloride (3 mg/kg n = 5). Both the phasic and tonic dopamine responses in the NAcc were augmented by the injection of cocaine compared to saline control. The phasic and tonic levels changed by approximately x2.4 and x1.9, respectively. These increases were largely consistent with previous studies using FSCV and microdialysis. However, the minimal disruption/disturbance of neuronal tissue by the CFM may explain why the baseline tonic dopamine values (134 ± 32 nM) measured by M-CSWV were found to be 10-fold higher when compared to conventional microdialysis. In this study, we demonstrated phasic dopamine dynamics in the NAcc with acute cocaine administration. M-CSWV was able to record rapid changes in tonic levels of dopamine, which cannot be achieved with other current voltammetric techniques. Taken together, M-CSWV has the potential to provide an unprecedented level of physiologic insight into dopamine signaling, both in vitro and in vivo , which will significantly enhance our understanding of neurochemical mechanisms underlying psychiatric conditions.
Changing Emotions
Publisher: Psychology Press
Date: 15-02-2013
Developmental perspectives on methamphetamine abuse: Exploring adolescent vulnerabilities on brain and behavior.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.PNPBP.2017.11.010
Abstract: Most people that experience illicit drugs do so for the first time during adolescence, and meth hetamine (meth) is no exception. Therefore, research into the effects of meth should highlight the adolescent period. Despite this, the vast majority of current literature has mainly focused on meth exposure during adulthood. In this review, we first describe existing literature that compares the behavioral effects of meth where exposure occurs in adolescence compared to adulthood. Given that there are actually very few such studies, we also look at what is known about neural effects of meth in the adult brain, and relate these to normal neural development occurring during the adolescent period to establish how meth may target maturing regions and related neurochemistry. What emerges overall is that adolescents appear to be more vulnerable to the rewarding and reinforcing effects of meth, and that meth indeed has effects on areas that are in flux during adolescence. However, there is some evidence for a paradoxical resistance to the neurotoxic effects during this period. We highlight the need for further age-related research to better understand, treat, and prevent meth use disorders and addiction in general.
Co-Expression Networks Unveiled Long Non-Coding RNAs as Molecular Targets of Drugs Used to Treat Bipolar Disorder
Publisher: Frontiers Media SA
Date: 08-04-2022
DOI: 10.3389/FPHAR.2022.873271
Abstract: Long non-coding RNAs (lncRNAs) may play a role in psychiatric diseases including bipolar disorder (BD). We investigated mRNA-lncRNA co-expression patterns in neuronal-like cells treated with widely prescribed BD medications. The aim was to unveil insights into the complex mechanisms of BD medications and highlight potential targets for new drug development. Human neuronal-like (NT2-N) cells were treated with either lamotrigine, lithium, quetiapine, valproate or vehicle for 24 h. Genome-wide mRNA expression was quantified for weighted gene co-expression network analysis (WGCNA) to correlate the expression levels of mRNAs with lncRNAs. Functional enrichment analysis and hub lncRNA identification was conducted on key co-expressed modules associated with the drug response. We constructed lncRNA-mRNA co-expression networks and identified key modules underlying these treatments, as well as their enriched biological functions. Processes enriched in key modules included synaptic vesicle cycle, endoplasmic reticulum-related functions and neurodevelopment. Several lncRNAs such as GAS6-AS1 and MIR100HG were highlighted as driver genes of key modules. Our study demonstrates the key role of lncRNAs in the mechanism(s) of action of BD drugs. Several lncRNAs have been suggested as major regulators of medication effects and are worthy of further investigation as novel drug targets to treat BD.
Juvenile female rats, but not male rats, show renewal, reinstatement, and spontaneous recovery following extinction of conditioned fear
Publisher: Cold Spring Harbor Laboratory
Date: 15-11-2017
Abstract: Anxiety disorders emerge early, and girls are significantly more likely to develop anxiety compared to boys. However, sex differences in fear during development are poorly understood. Therefore, we investigated juvenile male and female rats in the relapse behaviors following extinction of conditioned fear. In all experiments, 18-d-old rats first received three white-noise–footshock pairings on day 1. On day 2, extinction involved 60 white-noise alone trials. In experiment 1, we examined renewal by testing the rats in either the same or different context as extinction on day 3. Male rats did not show renewal, however, female rats showed renewal. Experiment 2 investigated reinstatement by giving rats either a mild reminder footshock or context exposure on day 3. When tested the next day, male rats did not show reinstatement, whereas female rats showed reinstatement. Experiment 3 investigated spontaneous recovery by testing the rats either 1 or 5 d following extinction. Male rats did not show any spontaneous recovery whereas female rats did. Taken together, fear regulation appear to be different in males versus females from early in development, which may explain why girls are more prone to suffer from anxiety disorders compared to boys.
Knockdown of CRF1 Receptors in the Ventral Tegmental Area Attenuates Cue- and Acute Food Deprivation Stress-Induced Cocaine Seeking in Mice
Publisher: Society for Neuroscience
Date: 27-08-2014
DOI: 10.1523/JNEUROSCI.4763-12.2014
Abstract: Corticotrophin-releasing factor (CRF) modulates the influence of stress on cocaine reward and reward seeking acting at multiple sites, including the ventral tegmental area (VTA). There is controversy, however, concerning the contribution of CRF receptor type 1 (CRFR1) to this effect and whether CRF within the VTA is involved in other aspects of reward seeking independent of acute stress. Here we examine the role of CRFR1 within the VTA in relation to cocaine and natural reward using viral delivery of short hairpin RNAs (lenti-shCRFR1) and investigate the effect on operant self-administration and motivation to self-administer, as well as stress- and cue-induced reward seeking in mice. While knockdown of CRFR1 in the VTA had no effect on self-administration behavior for either cocaine or sucrose, it effectively blocked acute food deprivation stress-induced reinstatement of cocaine seeking. We also observed reduced cue-induced cocaine seeking assessed in a single extinction session after extended abstinence, but cue-induced sucrose seeking was unaffected, suggesting dissociation between the contribution of CRFR1 in the VTA in cocaine reward and sucrose and cocaine seeking. Further, our data indicate a role for VTA CRFR1 signaling in cocaine seeking associated with, and independent of, stress potentially involving conditioning and/or salience attribution of cocaine reward-related cues. CRFR1 signaling in the VTA therefore presents a target for convergent effects of both cue- and stress-induced cocaine-seeking pathways.
Assessing methamphetamine-related cue reactivity in people with methamphetamine use disorder relative to controls
Publisher: Elsevier BV
Date: 12-2021
Investigating the role of dopamine receptor- and parvalbumin-expressing cells in extinction of conditioned fear
Publisher: Elsevier BV
Date: 11-2017
DOI: 10.1016/J.NLM.2017.08.009
Abstract: The present study examined the pattern of activation of neurons that express dopamine receptors 1 and 2 (D1R and D2R), and parvalbumin (PV) in mice that underwent extinction of a fear memory. Adult male transgenic mice expressing D1R or D2R tagged with green fluorescent protein (GFP) were conditioned with 6 tone-shock pairings. The following day they were randomly ided into one of four experimental groups: extinction, retrieval, context or handled. Extinction groups were exposed to 45 tone presentations, retrieval groups were exposed to 5 tone presentations and the context groups were exposed to the chamber without any tones. Ninety minutes following their assigned treatment, mice were perfused and brain tissue processed for Fos/GFP/PV immunohistochemistry. Quantification of immunoreactivity revealed that extinction resulted in changes in the infralimbic cortex including increased Fos expression and a decrease in the number of D2R+ cells compared to all other groups. Conversely, fear memory retrieval resulted in increased activation of D2R+ cells in the prelimbic cortex compared to all other groups. Additional changes were observed in the extinction and retrieval groups that were different to the handled group, but not to the context group, which highlights that there is overlapping neurocircuitry between extinction and retrieval of fear memory, as well as with context exposure. These results provide novel insights into the roles of specific dopamine receptor subtypes, which will be valuable for informing future research that aims to strengthen extinction learning via dopaminergic mechanisms.
Role of cues and contexts on drug-seeking behaviour
Publisher: Wiley
Date: 02-07-2014
DOI: 10.1111/BPH.12735
The Role of Mitogen-Activated Protein Kinase in Treatment Strategies for Fear and Drug Addiction
Publisher: InTech
Date: 05-06-2012
DOI: 10.5772/36756
The effect of the mGlu5 negative allosteric modulator MTEP and NMDA receptor partial agonist D-cycloserine on Pavlovian conditioned fear
Publisher: Oxford University Press (OUP)
Date: 27-03-2014
A developmental dissociation in reinstatement of an extinguished fear response in rats
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.NLM.2007.03.004
Abstract: Recently, studies from our laboratory have shown that 16-day-old rats, in contrast to 23-day-old rats, fail to show either ABA renewal or recovery of an extinguished fear response following a pre-test injection of FG7142 [Kim, J. H. & Richardson, R. (2007). A developmental dissociation of context and GABA effects on extinguished fear in rats. Behavioral Neuroscience Yap & Richardson, unpublished data]. The present study, using freezing as a measure of learned fear, extends these findings by examining whether there is a developmental difference in susceptibility to reinstatement following extinction. 16- and 23-day-old rats were trained to fear a white-noise conditioned stimulus (CS) by pairing it with a shock unconditioned stimulus (US). This fear was subsequently extinguished by non-reinforced presentations of the CS. Some rats received a post-extinction Reminder which consisted of a single presentation of a reduced-intensity US. Experiments 1 and 2 demonstrated that this Reminder was effective in reinstating extinguished fear in 23-day-olds, and that this reinstatement effect was context-specific in rats this age. In contrast, 16-day-old rats failed to show the reinstatement effect in either experiment. The failure to observe a post-extinction reinstatement effect in the 16-day-olds was not due to a general ineffectiveness of the Reminder treatment at this age because it did alleviate spontaneous forgetting in rats this age (Experiment 3). Taken together, the results suggest that fundamentally different processes may mediate extinction early in development compared to later in development.
Updating memories: Changing the involvement of the prelimbic cortex in the expression of an infant fear memory
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.NEUROSCIENCE.2012.06.038
Abstract: Recent work has found that infant rats (postnatal day (P) 18) do not require the prelimbic cortex (PL) to express learned fear, whereas older animals (adults and juveniles) do. In other words, there is a switch from a PL-independent fear expression system during infancy to a PL-dependent system later in life. The present study investigated whether the PL would be involved in fear expression in rats trained at P17 but tested at P23 (that is, as juveniles). The first two experiments showed that PL involvement in fear expression was determined by the age of the animal at the time of training rather than the animal's age at the time of test. More specifically, experiment 1 showed that expression of learned fear (measured by freezing, and elicited by a white noise previously paired with a shock) was PL-independent for memories that were acquired when the rat was P17 but then tested at P23. In experiment 2, rats trained at P23, when the PL is functionally mature, still required the PL to express fear when tested at P37. In the last experiment, using two different reactivation procedures, we showed that it is possible to update an infant memory and switch it from being PL-independent to being PL-dependent. Combined, these results have important implications for our understanding of the neural circuitry underlying fear expression across development and show that, at least in some cases, expression of fear responses learned early in life remain PL-independent even as the animal matures.
Reducing Fear During Childhood to Prevent Anxiety Disorders Later: Insights From Developmental Psychobiology
Publisher: SAGE Publications
Date: 24-08-2017
Abstract: Anxiety disorders are neurodevelopmental with the median age of onset 10 to 11 years, but developmental processes underlying fear and anxiety are rarely investigated. In the last decade, however, developmental rodent studies have increased our understanding of how to treat and prevent the persistence of anxiety. Behavioral findings from rodent studies match the observations in anxious children, and the neural and molecular findings help explain why anxiety disorders are indeed neurodevelopmental. Extinction processes that are involved in cognitive-behavioral therapy appear particularly effective in children compared with older populations. Policy should mandate school psychologists and government subsidies for therapy sessions to increase children’s mental-health-service utilization. Funding bodies also should challenge anxiety studies exclusively targeting adults to include younger people to investigate why anxiety disorders are developmental disorders and focus more on preventing their persistence later in life.
DOPAMAP, high-resolution images of dopamine 1 and 2 receptor expression in developing and adult mouse brains
Publisher: Springer Science and Business Media LLC
Date: 19-04-2022
DOI: 10.1038/S41597-022-01268-8
Abstract: The dopaminergic system undergoes major reorganization during development, a period especially vulnerable to mental disorders. Forebrain neurons expressing dopamine 1 and 2 receptors (D1R and D2R, respectively) play a key role in this system. However, neuroanatomical information about the typical development of these neurons is sparse and scattered across publications investigating one or a few brain regions. We here present a public online collection of microscopic images of immunohistochemically stained serial sections from male and female mice at five stages of development (postnatal day 17 (P17), P25, P35, P49, and adult), showing the distribution of D1R and D2R expressing neurons across the forebrain. All images from adult brains are registered to the Allen Mouse brain Common Coordinate Framework, while images from P17-P35 age groups are registered to spatially modified atlas versions matching the morphology of young brains. This online resource provides microscopic visualization of the developing dopaminergic system in mice, which is suitable as a benchmark reference for performing new experiments and building computational models of the brain.
Sex-dependent effects of chronic exercise on cognitive flexibility but not hippocampal Bdnf in aging mice
Publisher: Portland Press Ltd.
Date: 05-01-2022
DOI: 10.1042/NS20210053
Abstract: Cognitive impairments associated with advanced age involve alterations in the hippoc us that changes with experience throughout life. The hippoc us is critical for cognitive flexibility involved with extinction and reinstatement of conditioned fear. It is widely accepted that regular exercise can be beneficial for hippoc al function. Therefore, we asked whether chronic voluntary exercise in middle-aged mice can improve extinction and/or reinstatement of conditioned fear compared with standard-housing. Eight-month-old male and female C57Bl/6J mice had access to a running wheel or remained in standard-housing until 11 months of age. Alongside control standard-housed young adult (3-month-old) mice, they received tone–footshock pairings, which were subsequently extinguished with tone-alone presentations the next day. Half of the mice then received a reminder in the form of a single footshock. Male and female 11-month-old mice housed in standard conditions exhibited impaired reinstatement compared with young adult mice. However, for males that had access to a running wheel from 8 months of age, the reminder treatment rescued reinstatement ability. This was not observed in females. Additionally, exercise during middle age in both sexes increased expression of brain-derived neurotrophic factor (Bdnf) mRNA in the hippoc us, specifically exon 4 mRNA. These results show that, at least for males, physical exercise is beneficial for reducing age-related decline in cognitive abilities. Despite not affecting reinstatement, exercise also increased Bdnf gene expression in the female hippoc us, which could potentially benefit other forms of hippoc us-dependent cognition.
Immunohistochemical Analyses of Long-Term Extinction of Conditioned Fear in Adolescent Rats
Publisher: Oxford University Press (OUP)
Date: 24-06-2010
Abstract: Adolescence is a period of heightened emotional reactivity and vulnerability to poor outcomes (e.g., suicide, anxiety, and depression). Recent human and animal neuroimaging studies suggest that dramatic changes in prefrontal cortical areas during adolescence are involved in these effects. The present study explored the functional implications of prefrontal cortical changes during adolescence by examining conditioned fear extinction in adolescent rats. Experiment 1 showed that preadolescent (i.e., postnatal day [P] 24), adolescent (P35), and adult (P70) rats express identical extinction acquisition following 3 white-noise conditioned stimulus (CS) and shock pairings. When tested the next day, however, adolescent rats showed almost complete failure to maintain extinction of CS-elicited freezing compared with P24 and P70 rats. It was observed in experiment 2 that following extinction, P24 and P70 rats express significantly elevated levels of phosphorylated mitogen-activated protein kinase (pMAPK) in the infralimbic cortex (IL) compared with adolescent rats. Interestingly, adolescent rats successfully exhibited long-term extinction if the amount of extinction training was doubled (experiment 3). More extinction training also led to increased phosphorylation of MAPK in the IL in these rats. These findings suggest that adolescents are less efficient in utilizing prefrontal areas, which may lead to an impairment in the maintenance of extinguished behavior.
Metformin is Protective Against the Development of Mood Disorders
Publisher: Georg Thieme Verlag KG
Date: 28-09-2022
DOI: 10.1055/A-1936-3580
Abstract: Introduction Mood disorders are a major cause of disability, and current treatment options are inadequate for reducing the burden on a global scale. The aim of this project was to identify drugs suitable for repurposing to treat mood disorders. Methods This mixed-method study utilized gene expression signature technology and pharmacoepidemiology to investigate drugs that may be suitable for repurposing to treat mood disorders. Results The transcriptional effects of a combination of drugs commonly used to treat mood disorders included regulation of the steroid and terpenoid backbone biosynthesis pathways, suggesting a mechanism involving cholesterol biosynthesis, and effects on the thyroid hormone signaling pathway. Connectivity Map analysis highlighted metformin, an FDA-approved treatment for type 2 diabetes, as a drug having global transcriptional effects similar to the mood disorder drug combination investigated. In a retrospective cohort study, we found evidence that metformin is protective against the onset of mood disorders. Discussion These results provide proof-of-principle of combining gene expression signature technology with pharmacoepidemiology to identify potential novel drugs for treating mood disorders. Importantly, metformin may have utility in the treatment of mood disorders, warranting future randomized controlled trials to test its efficacy.
Assessment of conditioned fear extinction in male and female adolescent rats
Publisher: Elsevier BV
Date: 06-2020
Early life stress alters pituitary growth during adolescence-A longitudinal study
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.PSYNEUEN.2015.01.005
Abstract: The pituitary gland is integral in mediating the stress-response via its role in hypothalamic-pituitary-adrenal (HPA) axis function. Pituitary gland volume (PGV) is altered in stress-related psychopathology, and one study to date has shown stress to be associated with age-related PGV change during adolescence. The current study investigated the effects of a number of different types of early life (i.e., childhood and adolescent) stress (including childhood maltreatment, stressful life events, and maternal affective behavior) on PGV development from mid- to late adolescence using a longitudinal design. The influence of PGV development on depressive and anxiety symptoms was also investigated. Ninety one (49 male) adolescents took part in mother-child dyadic interaction tasks when they were approximately 12 years old, reported on childhood maltreatment and stressful life events when they were approximately 15 years old, and underwent two waves of structural magnetic resonance imaging (MRI) scans, when they were approximately 16 and 19 years old. Results revealed that childhood maltreatment predicted accelerated PGV development in females, and maternal dysphoric behavior predicted accelerated PGV development in the whole s le. PGV development was not associated with depressive or anxiety symptoms. These results suggest an effect of early life stress on altered HPA axis function across mid- to late adolescence. Further research is required to assess functional implications and whether these changes might be associated with risk for subsequent psychopathology.
Context fear learning and renewal of extinguished fear are dissociated in juvenile female rats
Publisher: Wiley
Date: 02-07-2019
DOI: 10.1002/DEV.21888
Abstract: Extinction is the decrease in emotion to a cue that was previously associated with an emotionally significant event. It involves repeated presentation of the cue without any consequences. In adult animals, extinguished fear to a cue can return if the cue is presented in a different environment/context to where extinction occurred, referred to as renewal. We have previously reported that developing female, but not male, rats show renewal. This study investigates whether the ability of developing female rats to show renewal is related to their ability in fear conditioning to the context. Additionally, facilitation of context conditioning by weaning previously shown in male rats was tested in developing female rats. In experiment 1, postnatal day 25 (P25) and P18 female rats showed renewal. P25 rats show more fear overall, suggesting a weaker extinction recall in this age. Experiment 2 tested context- and cue-elicited fear either immediately or 24 hr following conditioning. At the immediate test, P18 rats showed less context-fear compared with P25 rats. All rats showed low levels of context-fear at the 24 hr test. There were no age differences in cued fear. Weaning at P21 did not affect context or cue memory in P25 female rats. These findings suggest that the ability to form contextual fear memory is unrelated to the expression of renewal in juvenile female rats.
Effects of Methamphetamine Exposure on Fear Learning and Memory in Adult and Adolescent Rats.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2019
DOI: 10.1007/S11064-019-02845-X
Abstract: Meth hetamine (meth) use is often comorbid with anxiety disorders, with both conditions predominant during adolescence. Conditioned fear extinction is the most widely used model to study the fear learning and regulation that are relevant for anxiety disorders. The present study investigates how meth binge injections or meth self-administration affect subsequent fear conditioning, extinction and retrieval in adult and adolescent rats. In experiment 1, postnatal day 35 (P35-adolescent) and P70 (adult) rats were intraperitoneally injected with increasing doses of meth across 9 days. At P50 or P85, they underwent fear conditioning followed by extinction and test. In experiments 2a-c, P35 or P70 rats self-administered meth for 11 days then received fear conditioning at P50 or P85, followed by extinction and test. We observed that meth binge exposure caused a significant disruption of extinction retrieval in adult but not adolescent rats. Interestingly, meth self-administration in adolescence or adulthood disrupted acquisition of conditioned freezing in adulthood. Meth self-administration in adolescence did not affect conditioned freezing in adolescence. These results suggest that intraperitoneal injections of high doses of meth and meth self-administration have dissociated effects on fear conditioning and extinction during adulthood, while adolescent fear conditioning and extinction are unaffected.
Postnatal developmental trajectory of dopamine receptor 1 and 2 expression in cortical and striatal brain regions
Publisher: Wiley
Date: 18-12-2018
DOI: 10.1002/CNE.24574
Abstract: Healthy brain function requires a balance between the activity of dopamine receptor 1 (D1) and dopamine receptor 2 (D2). Alterations in this balance increase the risk for numerous developmental brain disorders. Indeed, D1 and D2 expression fluctuates throughout maturation, although there is conflicting evidence regarding the precise changes that occur. Here, we used stereology to investigate the developmental changes in the number of D1- or D2-expressing neurons in the prelimbic cortex, infralimbic cortex (IL), insula cortex, dorsal striatum, and ventral striatum of female and male mice with green fluorescent protein-tagged D1 or D2. Postnatal day 17, 25, 35, 49, and 70 were examined to cover juvenility to adulthood. In all regions, analysis of D1 density compared to D2 density within each sex seldom detected effects or interactions involving age. However, D1:D2 density ratio changed across age depending on sex. In the IL, D1:D2 density ratio increased in females from adolescence, whereas it was stable in males. In the insula cortex, D1:D2 ratio initially increased in males but decreased in females from juvenility to preadolescence. The ratio then increased in males and females from adolescence to adulthood, with males showing a more dramatic increase. In both the dorsal and ventral striatum, the ratio increased from adolescence. In all regions, females had a higher ratio compared to males throughout maturation except in the insula cortex at P25. These comprehensive observations are novel, and highlight how the maturational changes in the expression of these receptors may contribute to developmental disorders.
Gene-Targeted, CREB-Mediated Induction of ΔFosB Controls Distinct Downstream Transcriptional Patterns Within D1 and D2 Medium Spiny Neurons
Publisher: Elsevier BV
Date: 10-2021
Dissociated roles of dorsal and ventral hippocampus in recall and extinction of conditioned fear in male and female juvenile rats
Publisher: Elsevier BV
Date: 07-2020
Hippocampal and Prefrontal Projections to the Basal Amygdala Mediate Contextual Regulation of Fear after Extinction
Publisher: Society for Neuroscience
Date: 23-11-2011
DOI: 10.1523/JNEUROSCI.4095-11.2011
Abstract: Knowing when and where to express fear is essential to survival. Recent work in fear extinction paradigms reveals that the contextual regulation of fear involves a neural network involving the hippoc us, medial prefrontal cortex, and amygdala. The amygdaloid basal nuclei (BA) receive convergent input from the ventral hippoc us (VH) and prelimbic (PL) prefrontal cortex and may integrate VH and PL input to regulate fear expression. To examine the functional organization of this neural circuit, we used cellular imaging of c-fos expression in anatomically defined neuronal populations and circuit disconnections to identify the pathways involved in the contextual control of extinguished fear. Before behavioral testing, we infused a retrograde tracer into the amygdala to label BA-projecting neurons in VH and PL. Rats then underwent fear conditioning and extinction and were tested for their fear to the extinguished conditioned stimulus (CS) in either the extinction context or in another context freezing behavior served as the index of conditional fear. CS presentation outside the extinction context renewed conditional freezing and was associated with significantly more c-fos expression in BA-projecting neurons in the VH and PL than that induced by CS presentation in the extinction context. We next examined whether direct or indirect projections of VH to BA mediate fear renewal. Interestingly, disconnections of the VH from either the BA or PL eliminated renewal. These findings suggest that convergent inputs from both the VH and PL in the BA mediate the contextual control of fear after extinction.
New Findings on Extinction of Conditioned Fear Early in Development: Theoretical and Clinical Implications
Publisher: Elsevier BV
Date: 02-2010
DOI: 10.1016/J.BIOPSYCH.2009.09.003
Abstract: Research with adult animals suggests that extinction depends, at least partly, on new inhibitory learning that is specific to the context in which it is learned. However, several recent studies show that extinction processes are dissociated across development. The present article reviews research on the behavioral and neurobiological mechanisms underlying extinction in developing rats. To summarize, postweanling aged rats (i.e., 24-day-olds) display adult-like extinction in that they show renewal, reinstatement, spontaneous recovery, and compound summation of extinguished stimuli. However, preweanling aged rats (i.e., 17-day-olds) do not show any of those behavioral phenomena. Pharmacological studies also show that reducing N-methyl-D-aspartate, gamma-aminobutryic acid, and opioid neurotransmission impairs extinction in 24-day-old rats, but extinction in P17 rats is only affected by the blocking of opioid neurotransmission. Lastly, extinction in 24-day-old rats involves the amygdala and the ventromedial prefrontal cortex (vmPFC), which are critical brain areas in the neural circuitry of extinction in adult rats. Interestingly, extinction in 17-day-old rats involves the amygdala but not the vmPFC. The existing models of extinction cannot account for these developmental differences. These findings showing that distinct processes mediate extinction at different stages of development may have significant clinical implications, which are discussed in this review.
Prefrontal-Amygdala Connectivity and State Anxiety during Fear Extinction Recall in Adolescents
Publisher: Frontiers Media SA
Date: 04-12-2017
Chronic voluntary alcohol consumption causes persistent cognitive deficits and cortical cell loss in a rodent model
Publisher: Springer Science and Business Media LLC
Date: 09-12-2019
DOI: 10.1038/S41598-019-55095-W
Abstract: Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. Despite this, addiction therapy does not address cognitive deficits, and there is poor understanding regarding the mechanisms that underlie this decline. We established a rodent model of chronic voluntary alcohol use to measure ensuing cognitive effects and underlying pathology. Rats had intermittent access to alcohol or an isocaloric solution in their home cage under voluntary 2-bottle choice conditions. In Experiments 1 and 2 cognition was assessed using operant touchscreen chambers. We examined performance in a visual discrimination and reversal task (Experiment 1), and a 5-choice serial reaction time task (Experiment 2). For Experiment 3, rats were perfused immediately after cessation of alcohol access period, and volume, cell density and microglial populations were assessed in the prefrontal cortex and striatum. Volume was assessed using the Cavalieri probe, while cell and microglial counts were estimated using unbiased stereology with an optical fractionator. Alcohol-exposed and control rats showed comparable acquisition of pairwise discrimination however, performance was impaired when contingencies were reversed indicating reduced behavioral flexibility. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue. Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies.
Role of Dopamine 2 Receptor in Impaired Drug-Cue Extinction in Adolescent Rats
Publisher: Oxford University Press (OUP)
Date: 05-03-2016
Repurposing Drugs via Network Analysis: Opportunities for Psychiatric Disorders
Publisher: MDPI AG
Date: 14-07-2022
DOI: 10.3390/PHARMACEUTICS14071464
Abstract: Despite advances in pharmacology and neuroscience, the path to new medications for psychiatric disorders largely remains stagnated. Drug repurposing offers a more efficient pathway compared with de novo drug discovery with lower cost and less risk. Various computational approaches have been applied to mine the vast amount of biomedical data generated over recent decades. Among these methods, network-based drug repurposing stands out as a potent tool for the comprehension of multiple domains of knowledge considering the interactions or associations of various factors. Aligned well with the poly-pharmacology paradigm shift in drug discovery, network-based approaches offer great opportunities to discover repurposing candidates for complex psychiatric disorders. In this review, we present the potential of network-based drug repurposing in psychiatry focusing on the incentives for using network-centric repurposing, major network-based repurposing strategies and data resources, applications in psychiatry and challenges of network-based drug repurposing. This review aims to provide readers with an update on network-based drug repurposing in psychiatry. We expect the repurposing approach to become a pivotal tool in the coming years to battle debilitating psychiatric disorders.
Extinction of Conditioned Fear in Adolescents and Adults: A Human fMRI Study
Publisher: Frontiers Media SA
Date: 08-01-2018
Developmental rodent models of fear and anxiety: from neurobiology to pharmacology
Publisher: Wiley
Date: 07-2014
DOI: 10.1111/BPH.12643
The Effects of 4-Methylethcathinone on Conditioned Place Preference, Locomotor Sensitization, and Anxiety-Like Behavior: A Comparison with Methamphetamine
Publisher: Oxford University Press (OUP)
Date: 26-11-2015
DOI: 10.1093/IJNP/PYV120
Cognition and Related Neural Findings on Methamphetamine Use Disorder: Insights and Treatment Implications From Schizophrenia Research
Publisher: Frontiers Media SA
Date: 17-12-2019
Differential involvement of the medial prefrontal cortex in the expression of learned fear across development.
Publisher: American Psychological Association (APA)
Date: 04-2012
DOI: 10.1037/A0027151
Abstract: Studies have shown that in adult animals the medial prefrontal cortex (mPFC) is a critical brain region involved in fear regulation, with the prelimbic (PL) subregion being important for fear expression. However, few studies have examined whether the PL cortex is also involved in fear expression in infant animals. Five experiments, using immunohistochemical and temporary inactivation procedures, assessed the role of the PL in the expression of learned fear in postnatal day (PND) 18 (infant) and PND25 (juvenile) rats. We found that in juvenile rats expressing fear (measured through freezing) there was an increase in the number of phosphorylated mitogen-activated protein kinase (pMAPK)-labeled neurons in the PL this increase was not observed in the infralimbic cortex. Furthermore, inactivation of the PL at test, using muscimol, decreased freezing in the juvenile rat. In contrast, expression of learned fear in infant rats did not require the PL, as there was neither an increase in the number of pMAPK-labeled cells in the PL nor was there any effect of PL inactivation on freezing levels. Taken together, these experiments suggest that a different neural circuitry underlies fear regulation early in life and that the lack of mPFC involvement may reflect a less flexible emotional regulation system in infant animals.
Adenosine 2A receptors modulate reward behaviours for methamphetamine
Publisher: Wiley
Date: 22-01-2015
DOI: 10.1111/ADB.12225
Abstract: Addiction to meth hetamine (METH) is a global health problem for which there are no approved pharmacotherapies. The adenosine 2A (A2 A ) receptor presents a potential therapeutic target for METH abuse due to its modulatory effects on striatal dopamine and glutamate transmission. Notably, A2 A receptor signalling has been implicated in the rewarding effects of alcohol, cocaine and opiates yet, the role of this receptor in METH consumption and seeking is essentially unknown. Therefore, the current study used A2 A knockout (KO) mice to assess the role of A2 A in behaviours relevant to METH addiction. METH conditioned place preference was absent in A2 A KO mice compared with wild-type (WT) littermates. Repeated METH treatment produced locomotor sensitization in both genotypes however, sensitization was attenuated in A2 A KO mice in a dose-related manner. METH intravenous self-administration was intact in A2 A KO mice over a range of doses and schedules of reinforcement. However, the motivation to self-administer was reduced in A2 A KO mice. Regression analysis further supported the observation that the motivation to self-administer METH was reduced in A2 A KO mice even when self-administration was similar to WT mice. Sucrose self-administration was also reduced in A2 A KO mice but only at higher schedules of reinforcement. Collectively, these data suggest that A2 A signalling is critically required to integrate rewarding and motivational properties of both METH and natural rewards.
Auditory fear conditioning alters neural gain in the cochlear nucleus: a wireless neural recording study in freely behaving rats
Publisher: Portland Press Ltd.
Date: 16-11-2020
DOI: 10.1042/NS20200009
Abstract: Anxiety disorders involve distorted perception of the world including increased saliency of stress-associated cues. However, plasticity in the initial sensory regions of the brain following a fearful experience has never been examined. The cochlear nucleus (CN) is the first station in the central auditory system, with heterogeneous collections of neurons that not only project to but also receive projections from cortico-limbic regions, suggesting a potential for experience-dependent plasticity. Using wireless neural recordings in freely behaving rats, we demonstrate for the first time that neural gain in the CN is significantly altered by fear conditioning to auditory sequences. Specifically, the ventral subnuclei significantly increased firing rate to the conditioned tone sequence, while the dorsal subnuclei significantly decreased firing rate during the conditioning session overall. These findings suggest subregion-specific changes in the balance of inhibition and excitation in the CN as a result of conditioning experience. Heart rate was measured as the conditioned response (CR), which showed that while pre-conditioned stimulus (CS) responding did not change across baseline and conditioning sessions, significant changes in heart rate were observed to the tone sequence followed by shock. Heart-rate findings support acquisition of conditioned fear. Taken together, the present study presents first evidence for potential experience-dependent changes in auditory perception that involve novel plasticity within the first site of processing auditory information in the brain.
Extinction in preweanling rats does not involve NMDA receptors
Publisher: Elsevier BV
Date: 09-2010
DOI: 10.1016/J.NLM.2010.05.004
Abstract: Past research has shown that the N-methyl-d-aspartate receptor (NMDAr) is critically involved in the extinction of learned fear in adult rats with NMDAr antagonists impairing extinction retention and NMDAr agonists enhancing it. In the present study we examined the effects of the NMDAr antagonist MK-801 on extinction in the developing rat. In Experiment 1, rats were given pairings of a white-noise conditioned stimulus (CS) and a shock unconditioned stimulus (US) on postnatal day (P)16. An extinction session, where the CS was presented without the US, occurred on P17 or P24. Prior to extinction rats were injected with MK-801 or saline. All rats were tested for fear of the CS on P25, while drug free. Saline-treated rats exhibited good retention of extinction whether they were extinguished at P17 or P25. Rats treated with MK-801 exhibited impaired extinction retention but only if extinction occurred on P24. These findings show that extinction is NMDAr-dependent at P24 but NMDAr-independent at P17. Experiment 2 further examined the involvement of NMDA receptors in extinction at different stages of development by taking advantage of a finding from several recent studies on re-extinction. These studies have shown, in adult rats, a transition from NMDAr-dependent extinction to NMDAr-independent re-extinction. That is, if rats are trained, extinguished, re-trained to the same CS, and then extinguished again (i.e., re-extinction), then NMDA receptors are not required for extinction the second time. In Experiment 2, rats were trained to fear the CS at P16 this fear was extinguished at either P17 or P24. All rats were then re-trained to fear the CS at P25, re-extinguished at P26, and tested at P27. Prior to re-extinction, rats were injected with MK-801 or saline. Rats initially extinguished at P24, an age where NMDA receptors are involved in extinction, exhibited the transition to an NMDAr-independent re-extinction process. In contrast, rats initially extinguished at P17, an age where NMDA receptors are not involved in extinction, did not (i.e., these rats still exhibited an impairment in extinction retention if given MK-801 prior to re-extinction). Taken together, these findings demonstrate that a qualitatively different system mediates extinction early in life.
Immediate post-reminder injection of gamma-amino butyric acid (GABA) agonist midazolam attenuates reactivation of forgotten fear in the infant rat.
Publisher: American Psychological Association (APA)
Date: 2007
DOI: 10.1037/0735-7044.121.6.1328
Abstract: J. H. Kim, G. McNally, and R. Richardson (2006) reported that pretest injection of FG7142, a GABA inverse agonist, alleviated infantile amnesia in rats. From this, it was concluded that GABAergic neurotransmission is involved in the forgetting seen in the developing rat. The present study extends that finding by examining the role of GABA in the reactivation of a forgotten memory in the infant rat. Sixteen-day-old rats were conditioned to fear a white noise. When tested 3 days later, rats that had not received a reminder treatment exhibited substantial forgetting. Reactivation of memory (as assessed by high levels of freezing) was observed in rats that were given a reminder shock and injected with saline the day before test. However, rats given a reminder shock and injected with midazolam immediately afterward failed to exhibit the reactivation effect. A subsequent experiment replicated this finding and further showed that midazolam did not reduce the memory reactivation effect when injected 2 hr after the reminder episode. From this, it appears that alterations in GABAergic neurotransmission may be an underlying process mediating memory reactivation in the infant rat.
Deep Brain Stimulation for Addictive Disorders—Where Are We Now?
Publisher: Springer Science and Business Media LLC
Date: 11-04-2022
DOI: 10.1007/S13311-022-01229-4
Abstract: In the face of a global epidemic of drug addiction, neglecting to develop new effective therapies will perpetuate the staggering human and economic costs of substance use. This review aims to summarize and evaluate the preclinical and clinical studies of deep brain stimulation (DBS) as a novel therapy for refractory addiction, in hopes to engage and inform future research in this promising novel treatment avenue. An electronic database search (MEDLINE, EMBASE, Cochrane library) was performed using keywords and predefined inclusion criteria between 1974 and 6/18/2021 (registered on Open Science Registry). Selected articles were reviewed in full text and key details were summarized and analyzed to understand DBS’ therapeutic potential and possible mechanisms of action. The search yielded 25 animal and 22 human studies. Animal studies showed that DBS of targets such as nucleus accumbens (NAc), insula, and subthalamic nucleus reduces drug use and seeking. All human studies were case series/reports (level 4/5 evidence), mostly targeting the NAc with generally positive outcomes. From the limited evidence in the literature, DBS, particularly of the NAc, appears to be a reasonable last resort option for refractory addictive disorders. We propose that future research in objective electrophysiological (e.g., local field potentials) and neurochemical (e.g., extracellular dopamine levels) biomarkers would assist monitoring the progress of treatment and developing a closed-loop DBS system. Preclinical literature also highlighted the prefrontal cortex as a promising DBS target, which should be explored in human research.
The effect of the μ-opioid receptor antagonist naloxone on extinction of conditioned fear in the developing rat
Publisher: Cold Spring Harbor Laboratory
Date: 17-02-2009
DOI: 10.1101/LM.1282309
Abstract: Several recent studies report that neurotransmitters that are critically involved in extinction in adult rats are not important for extinction in young rats. Specifically, pretest injection of the γ-aminobutryic acid (GABA) receptor inverse agonist FG7142 has no effect on extinction in postnatal day (P)17 rats, although it reverses extinction in P24 rats as reported by Kim and Richardson in an earlier paper. Further, pre-extinction injection of the N -methyl- d -aspartate (NMDA) receptor antagonist MK-801 has no effect on extinction in P17 rats, whereas it impairs long-term extinction in P24 rats as per Langton and colleagues in an earlier work. These findings indicate that extinction in P17 rats is qualitatively different from extinction in older rats. The present study examines the involvement of the endogenous opioid system in extinction in the developing rat using systemic injections of the μ-opioid receptor antagonist naloxone. Experiment 1 showed that injection of naloxone before extinction training disrupted the acquisition of extinction in both P17 and P24 rats. This effect was dependent on central rather than peripheral μ-opioid receptors (Experiment 2), and neither pre-test nor post-extinction injection of naloxone had effects on extinction (Experiments 3 and 4). Taken together, these findings indicate that opioid neurotransmission, in contrast to GABA and NMDA activity, is critical for extinction acquisition across development.
The Effect of Temporary Amygdala Inactivation on Extinction and Reextinction of Fear in the Developing Rat: Unlearning as a Potential Mechanism for Extinction Early in Development
Publisher: Society for Neuroscience
Date: 06-02-2008
DOI: 10.1523/JNEUROSCI.4736-07.2008
Abstract: It is well accepted that fear extinction does not cause erasure of the original conditioned stimulus (CS)–unconditioned stimulus association in the adult rat because the extinguished fear often returns (e.g., renewal and reinstatement). Furthermore, extinction is NMDA and GABA dependent, showing that extinction involves new inhibitory learning. We have recently observed each of these extinction-related phenomena in 24-d-old but not in 17-d-old rats. These results suggest that different neural processes mediate extinction early in development. However, the neural processes underlying extinction in the developing rat are unknown. Therefore, the present study investigated amygdala involvement in extinction and reextinction during development. In experiment 1, temporary inactivation of the amygdala (using bupivacaine, a sodium channel modulator) during extinction training impaired extinction of conditioned fear in 17- and 24-d-old rats. In experiment 2, 17- and 24-d-old rats were conditioned, extinguished, and then reconditioned to the same CS. After reconditioning, the CS was reextinguished at this time, some rats at each age had their amygdala temporarily inactivated. Reextinction was amygdala independent in 24-d-old rats, as previously shown in adult rats. However, reextinction was still amygdala dependent in 17-d-old rats. In Experiment 3, the age at conditioning, reconditioning, reextinction, and test was held constant, but the age of initial extinction varied across groups reextinction was found to be amygdala independent if initial extinction occurred at 24 d of age but amygdala dependent if it occurred at 17 d of age. Consistent with previous findings, these results show that there are fundamental differences in the neural mechanisms of fear extinction across development.
Metabolic regulation to treat bipolar depression: mechanisms and targeting by trimetazidine
Publisher: Springer Science and Business Media LLC
Date: 29-06-2023
DOI: 10.1038/S41380-023-02134-8
Abstract: Bipolar disorder’s core feature is the pathological disturbances in mood, often accompanied by disrupted thinking and behavior. Its complex and heterogeneous etiology implies that a range of inherited and environmental factors are involved. This heterogeneity and poorly understood neurobiology pose significant challenges to existing drug development paradigms, resulting in scarce treatment options, especially for bipolar depression. Therefore, novel approaches are needed to discover new treatment options. In this review, we first highlight the main molecular mechanisms known to be associated with bipolar depression–mitochondrial dysfunction, inflammation and oxidative stress. We then examine the available literature for the effects of trimetazidine in said alterations. Trimetazidine was identified without a priori hypothesis using a gene-expression signature for the effects of a combination of drugs used to treat bipolar disorder and screening a library of off-patent drugs in cultured human neuronal-like cells. Trimetazidine is used to treat angina pectoris for its cytoprotective and metabolic effects (improved glucose utilization for energy production). The preclinical and clinical literature strongly support trimetazidine’s potential to treat bipolar depression, having anti-inflammatory and antioxidant properties while normalizing mitochondrial function only when it is compromised. Further, trimetazidine’s demonstrated safety and tolerability provide a strong rationale for clinical trials to test its efficacy to treat bipolar depression that could fast-track its repurposing to address such an unmet need as bipolar depression.
Recovery of fear memories in rats: Role of gamma-amino butyric acid (GABA) in infantile amnesia
Publisher: American Psychological Association (APA)
Date: 2006
Neurocircuitry of fear extinction in adult and juvenile rats
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.BBR.2018.06.001
Abstract: In contrast to adult rodents, juvenile rodents fail to show relapse following extinction of conditioned fear. Using different retrograde tracers injected into the infralimbic cortex (IL) and the ventral hippoc us (vHPC) in conjunction with c-Fos and parvalbumin (PV) immunochemistry, we investigated the neurocircuitry of extinction in juvenile and adult rats. Regardless of fear extinction or retrieval, juvenile rats had more c-Fos+ neurons in the basolateral amygdala (BLA) compared to adults, and showed a higher proportion of c-Fos+ IL-projecting neurons. Adult rats had more activated vHPC-projecting BLA neurons following extinction compared to retrieval, a difference not observed in juvenile rats. The number of activated vHPC- or IL-projecting BLA neurons was significantly correlated with freezing levels in adult, but not juvenile, rats. We also identified activated neurons in the BLA that simultaneously project to the IL and vHPC in the retrieval groups at both ages. This study provides novel insight into the neural process underlying extinction, especially in the juvenile period.
CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use
Publisher: Elsevier BV
Date: 03-2023
DOI: 10.1016/J.BIOPSYCH.2022.07.022
Abstract: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice. To investigate the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. Together, these findings point to the CREB-Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine.
A Review of Preclinical Studies to Understand Fear During Adolescence
Publisher: Informa UK Limited
Date: 02-2015
DOI: 10.1111/AP.12066
Netrin-1 receptor-deficient mice show age-specific impairment in drug-induced locomotor hyperactivity but still self-administer methamphetamine
Publisher: Springer Science and Business Media LLC
Date: 03-07-2013
DOI: 10.1007/S00213-013-3187-5
Abstract: The mesocorticolimbic dopamine system undergoes significant reorganization of neuronal connectivity and functional refinement during adolescence. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, is involved in this reorganization. Previous studies have shown that adult mice with a heterozygous (het) loss-of-function mutation in DCC exhibit impairments in sensitization and conditioned place preference (CPP) to psychostimulants. However, the commonly abused psychostimulant meth hetamine (METH) has not been assessed, and the role of DCC in drug self-administration remains to be established. Using dcc het mice and wildtype (WT) littermates, we extended previous findings on dcc haplodeficiency by examining self-administration of METH in adult mice, including cue-induced drug seeking following abstinence. We also examined hyperactivity, sensitization, and CPP to a METH-paired context in adult and adolescent mice. While adult dcc het mice expressed largely similar METH self-administration and cue-induced drug seeking as WT littermates, they failed to modulate responding according to dose of METH. Compared to WT, both adult and adolescent dcc het mice expressed impaired locomotor hyperactivity to acute METH but nevertheless showed comparable behavioral sensitization. Conditioned hyperactivity increased with age in WT but not in dcc het mice. Impaired METH-induced hyperactivity and dose-related responding in adult dcc het mice suggest that reduced DCC alters METH-related behaviors. Adolescence is identified as a vulnerable period during which impairment in hyperactivity due to reduced DCC can be overcome with repeated METH injections. Nevertheless, DCC appears to have a somewhat limited role in METH-consumption and seeking following abstinence.
Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring
Publisher: Springer Science and Business Media LLC
Date: 14-06-2016
DOI: 10.1038/TP.2016.109
Abstract: Recent studies have suggested that physiological and behavioral traits may be transgenerationally inherited through the paternal lineage, possibly via non-genomic signals derived from the sperm. To investigate how paternal stress might influence offspring behavioral phenotypes, a model of hypothalamic–pituitary–adrenal (HPA) axis dysregulation was used. Male breeders were administered water supplemented with corticosterone (CORT) for 4 weeks before mating with untreated female mice. Female, but not male, F1 offspring of CORT-treated fathers displayed altered fear extinction at 2 weeks of age. Only male F1 offspring exhibited altered patterns of ultrasonic vocalization at postnatal day 3 and, as adults, showed decreased time in open on the elevated-plus maze and time in light on the light–dark apparatus, suggesting a hyperanxiety-like behavioral phenotype due to paternal CORT treatment. Interestingly, expression of the paternally imprinted gene Igf2 was increased in the hippoc us of F1 male offspring but downregulated in female offspring. Male and female F2 offspring displayed increased time spent in the open arm of the elevated-plus maze, suggesting lower levels of anxiety compared with control animals. Only male F2 offspring showed increased immobility time on the forced-swim test and increased latency to feed on the novelty-supressed feeding test, suggesting a depression-like phenotype in these animals. Collectively, these data provide evidence that paternal CORT treatment alters anxiety and depression-related behaviors across multiple generations. Analysis of the small RNA profile in sperm from CORT-treated males revealed marked effects on the expression of small noncoding RNAs. Sperm from CORT-treated males contained elevated levels of three microRNAs, miR-98, miR-144 and miR-190b, which are predicted to interact with multiple growth factors, including Igf2 and Bdnf . Sustained elevation of glucocorticoids is therefore involved in the transmission of paternal stress-induced traits across generations in a process involving small noncoding RNA signals transmitted by the male germline.
Knockdown of corticotropin-releasing factor 1 receptors in the ventral tegmental area enhances conditioned fear.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.EURONEURO.2016.06.002
Abstract: The neuropeptide corticotropin-releasing factor (CRF) coordinates the physiological and behavioural responses to stress. CRF receptors are highly expressed in the ventral tegmental area (VTA), an important region for motivated behaviour. Therefore, we examined the role of CRF receptor type 1 (CRFR1) in the VTA in conditioned fear, using a viral-mediated RNA interference approach. Following stereotaxic injection of a lentivirus that contained either shCRF-R1 or a control sequence, mice received tone-footshock pairings. Intra-VTA shCRF-R1 did not affect tone-elicited freezing during conditioning. Once conditioned fear was acquired, however, shCRF-R1 mice consistently showed stronger freezing to the tone even after extinction and reinstatement. These results implicate a novel role of VTA CRF-R1 in conditioned fear, and suggest how stress may modulate aversive learning and memory.
Aripiprazole Facilitates Extinction of Conditioned Fear in Adolescent Rats.
Publisher: Frontiers Media SA
Date: 09-05-2017
Prefrontal Dopaminergic Mechanisms of Extinction in Adolescence Compared to Adulthood in Rats
Publisher: Frontiers Media SA
Date: 22-02-2017
In vivo prion models and the disconnection between transmissibility and neurotoxicity
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1016/J.ARR.2017.03.007
Abstract: The primary causative event in the development of prion diseases is the misfolding of the normal prion protein (PrP
Fear Extinction across Development: The Involvement of the Medial Prefrontal Cortex as Assessed by Temporary Inactivation and Immunohistochemistry
Publisher: Society for Neuroscience
Date: 02-09-2009
DOI: 10.1523/JNEUROSCI.0596-09.2009
Abstract: Extinction in adult animals, including humans, appears to involve the medial prefrontal cortex (mPFC). However, the role of mPFC in extinction across development has not yet been studied. Given several recent demonstrations of developmental differences in extinction of conditioned fear at a behavioral level, different neural circuitries may mediate fear extinction across development. In all experiments, noise conditioned stimulus (CS) and shock unconditioned stimulus (US) were used. In experiment 1A, temporary unilateral inactivation of the mPFC during extinction training impaired long-term extinction the following day in postnatal day 24 (P24) rats but not in P17 rats. In experiment 1B, bilateral inactivation of the mPFC again failed to disrupt long-term extinction in P17 rats. In experiment 2, extinction training increased phosphorylated mitogen-activated protein kinase (pMAPK) in the mPFC for P24 rats but not for P17 rats, whereas rats of both ages displayed elevated pMAPK in the amygdala. Across both ages, “not trained,” “reactivated,” and “no extinction” control groups expressed very low numbers of pMAPK-immunoreactive (IR) neurons across both neural structures. This result indicates that the mere conditioning experience, the exposure to the CS, or the expression of CS-elicited fear in and of itself is not sufficient to explain the observed increase in pMAPK-IR neurons in the mPFC and/or the amygdala after extinction. Together, these findings show that extinction in P17 rats does not involve the mPFC, which has important theoretical and clinical implications for the treatment of anxiety disorders in humans.
Hippocampal neurogenesis mediates sex-specific effects of social isolation and exercise on fear extinction in adolescence
Publisher: Elsevier BV
Date: 11-2021
Insular cortex dopamine 1 and 2 receptors in methamphetamine conditioned place preference and aversion: Age and sex differences
Publisher: Portico
Date: 27-08-2021
Biological Mechanism(s) Underpinning the Association between Antipsychotic Drugs and Weight Gain
Publisher: MDPI AG
Date: 10-09-2021
DOI: 10.3390/JCM10184095
Abstract: Weight gain and consequent metabolic alterations are common side-effects of many antipsychotic drugs. Interestingly, several studies have suggested that improvement in symptoms and adverse metabolic effects are correlated. We used next generation sequencing data from NT-2 (human neuronal) cells treated with aripiprazole, amisulpride, risperidone, quetiapine, clozapine, or vehicle control, and compared with the Pillinger P-score (ranked from 0 to 1, indicating greater increase in weight gain and related metabolic parameters) to identify the genes most associated with the drugs’ propensity to cause weight gain. The top 500 genes ranked for their correlation with the drugs’ propensity to cause weight gain were subjected to pathway analysis using DAVID (NIH). We further investigated transcription factors (TFs) that are more likely to regulate the genes involved in these processes using the prediction tool of key TFs from TRRUST. The results suggest an enrichment for genes involved in lipid biosynthesis and metabolism, which are of interest for mechanisms underpinning weight-gain. The list of genes involved in the lipid pathways that correlated with weight gain was enriched for genes transcriptionally regulated by SREBF1 and SREBF2. Furthermore, quetiapine significantly increased the expression of SREBF1 and SREBF2 in NT-2 cells. Our results suggest that the effects of these antipsychotic drugs on lipid metabolism may be mediated, at least in part, via regulation of SREBF1/SREBF2 expression, with evidence of a direct effect of quetiapine on the expression of SREBF1/2. The effects of antipsychotic drugs on lipid metabolism may influence white matter structure (therapeutic effect) and the risk of weight gain, lipid disturbances, and, consequently, metabolic syndrome (adverse effects). Understanding the different molecular effects of these drugs could inform a personalized medicine approach in treating patients with schizophrenia.
Integrative Analyses of Transcriptomes to Explore Common Molecular Effects of Antipsychotic Drugs
Publisher: MDPI AG
Date: 06-07-2022
DOI: 10.3390/IJMS23147508
Abstract: There is little understanding of the underlying molecular mechanism(s) involved in the clinical efficacy of antipsychotics for schizophrenia. This study integrated schizophrenia-associated transcriptional perturbations with antipsychotic-induced gene expression profiles to detect potentially relevant therapeutic targets shared by multiple antipsychotics. Human neuronal-like cells (NT2-N) were treated for 24 h with one of the following antipsychotic drugs: amisulpride, aripiprazole, clozapine, risperidone, or vehicle controls. Drug-induced gene expression patterns were compared to schizophrenia-associated transcriptional data in post-mortem brain tissues. Genes regulated by each of four antipsychotic drugs in the reverse direction to schizophrenia were identified as potential therapeutic-relevant genes. A total of 886 genes were reversely expressed between at least one drug treatment (versus vehicle) and schizophrenia (versus healthy control), in which 218 genes were commonly regulated by all four antipsychotic drugs. The most enriched biological pathways include Wnt signaling and action potential regulation. The protein-protein interaction (PPI) networks found two main clusters having schizophrenia expression quantitative trait loci (eQTL) genes such as PDCD10, ANK2, and AKT3, suggesting further investigation on these genes as potential novel treatment targets.
Phosphorylation of mitogen-activated protein kinase in the medial prefrontal cortex and the amygdala following memory retrieval or forgetting in developing rats
Publisher: Elsevier BV
Date: 2012
DOI: 10.1016/J.NLM.2011.09.005
Abstract: We examined neuronal correlates of forgetting in rats by detection of phosphorylated mitogen-activated protein kinase (pMAPK) in the medial prefrontal cortex (mPFC) and amygdala. In Experiment 1, postnatal day (P)23 and P16 rats received paired noise CS-shock US presentations. When tested immediately after conditioning, P23 and P16 rats exhibited similar levels of conditioned fear when tested after 2 days, however, P16 rats showed poor CS-elicited freezing relative to P23 rats. In Experiment 2, P16 and P23 rats received either paired or unpaired CS-US presentations, and then were tested 48 h later. Consistent with Experiment 1, P16 rats showed forgetting whereas P23 rats exhibited good retention at test. Additionally, unpaired groups showed poor CS-elicited freezing at test. Immunohistochemistry showed that P23 and P16 rats given paired presentations exhibited significant elevation of pMAPK-immunoreactive (ir) neurons in the amygdala compared to rats given unpaired presentations. That is, MAPK phosphorylation in the amygdala tracked learning history rather than behavioral performance at test. In contrast, only the P23-paired group showed an elevated number of pMAPK-ir neurons in mPFC, indicating that MAPK phosphorylation in the mPFC tracks memory expression. Different test-perfusion intervals were employed in Experiment 3, which showed that the developmental dissociation in the pMAPK-ir neurons observed in the mPFC in Experiment 2 was not due to age differences in the rate of phosphorylation of MAPK. These findings provide initial evidence suggesting that while the mPFC is involved in memory retrieval, MAPK phosphorylation in the amygdala may be a persisting neural signature of fear memory.
Impaired Extinction Retention in Adolescent Rats: Effects of D-Cycloserine
Publisher: Springer Science and Business Media LLC
Date: 30-06-2010
DOI: 10.1038/NPP.2010.92
Past and current drug repurposing clinical trials to treat cognition in methamphetamine use: a scoping review of pharmacotherapy candidates
Publisher: Elsevier BV
Date: 03-2023
Associations between early life stress and anterior pituitary gland volume development – A novel index of long-term hypothalamic-pituitary-adrenal axis functioning
Publisher: Wiley
Date: 19-10-2021
DOI: 10.1002/DEV.22047
Abstract: Previous research has established associations between early life stress (ELS) and altered pituitary gland volume (PGV) growth during adolescence. The pituitary gland, however, is composed of an anterior and a posterior lobe with distinct histological and neuroendocrinological properties. While the anterior (but not posterior) pituitary gland is directly involved in the hypothalamic‐pituitary‐adrenal axis (HPAA) stress response, no studies have examined the effects of ELS on anterior PGV (aPGV). The present study investigated whether previously reported associations between ELS and PGV development during adolescence were driven by aPGV versus posterior PGV (pPGV). Ninety‐one adolescents (49 males) were included from a longitudinal, community‐based adolescent development study investigating risk for psychopathology. ELS (maternal affective behavior, childhood maltreatment, stressful life events) was assessed during early adolescence. Participants underwent two waves of structural magnetic resonance imaging during mid‐ and late‐adolescence, and aPGV and pPGV were manually traced. Regression analyses showed that childhood maltreatment predicted greater aPGV growth in females. This finding was stronger than that previously reported for PGV. No associations were found between ELS and pPGV development. Neither aPGV nor pPGV changes mediated associations between ELS and psychopathology. Results suggest that ELS may accelerate aPGV (but not pPGV) growth throughout adolescence. Investigating the development of aPGV, rather than PGV, represents a novel approach to studying the effects of stress on HPAA functioning.
Fear extinction in 17 day old rats is dependent on metabotropic glutamate receptor 5 signaling
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.BBR.2014.12.010
Abstract: We used pharmacological modulation of the mGlu5 receptor to investigate its role in the extinction of conditioned fear throughout development. In postnatal day (P) 17 rats, the positive allosteric modulator CDPPB facilitated, while the negative allosteric modulator MTEP impaired extinction. These drugs had no such effects on P24 or adult rats. These results establish a changing importance of mGlu5 in extinction of conditioned fear at distinct stages of development.
Youth is not wasted on the young: Commentary on a BBR themed issue on developmental regulation of memory in anxiety and addiction
Publisher: Elsevier BV
Date: 02-2016
Expression of Renewal Is Dependent on the Extinction-Test Interval Rather Than the Acquisition-Extinction Interval
Publisher: American Psychological Association (APA)
Date: 2009
DOI: 10.1037/A0015237
Abstract: A recent finding suggested that when extinction occurs shortly after acquisition, renewal of an extinguished fear response (fear-potentiated startle) to a light conditioned stimulus (CS) is diminished (Myers, Ressler, & Davis, 2006). The present study attempted to extend this finding using a white-noise CS and freezing as the behavioral measure of fear. In Experiments 1A and 1B, we observed renewal whether extinction occurred 10 min or 24 hr after acquisition. In contrast, renewal was not observed if test occurred 10 min after extinction (Experiment 2). Experiment 3 demonstrated that expression of extinction at the 10-min extinction-test interval was attenuated by a pretest subcutaneous injection of the gamma-aminobutyric acid (GABA) inverse agonist FG7142. These findings suggest that renewal is influenced more by the extinction-test interval than the acquisition-extinction interval. Further, the failure to see renewal 10 min after extinction suggests that there is a separate context memory that undergoes a different consolidation function than the CS-no US memory formed during extinction. Finally, the expression of extinction appears to be GABA dependent regardless of the extinction-test interval or the test context.
Effects of Psychotropic Drugs on Ribosomal Genes and Protein Synthesis
Publisher: MDPI AG
Date: 28-06-2022
DOI: 10.3390/IJMS23137180
Abstract: Altered protein synthesis has been implicated in the pathophysiology of several neuropsychiatric disorders, particularly schizophrenia. Ribosomes are the machinery responsible for protein synthesis. However, there remains little information on whether current psychotropic drugs affect ribosomes and contribute to their therapeutic effects. We treated human neuronal-like (NT2-N) cells with amisulpride (10 µM), aripiprazole (0.1 µM), clozapine (10 µM), lamotrigine (50 µM), lithium (2.5 mM), quetiapine (50 µM), risperidone (0.1 µM), valproate (0.5 mM) or vehicle control for 24 h. Transcriptomic and gene set enrichment analysis (GSEA) identified that the ribosomal pathway was altered by these drugs. We found that three of the eight drugs tested significantly decreased ribosomal gene expression, whilst one increased it. Most changes were observed in the components of cytosolic ribosomes and not mitochondrial ribosomes. Protein synthesis assays revealed that aripiprazole, clozapine and lithium all decreased protein synthesis. Several currently prescribed psychotropic drugs seem to impact ribosomal gene expression and protein synthesis. This suggests the possibility of using protein synthesis inhibitors as novel therapeutic agents for neuropsychiatric disorders.
The effect of the NMDA receptor antagonist MK-801 on the acquisition and extinction of learned fear in the developing rat
Publisher: Cold Spring Harbor Laboratory
Date: 25-09-2007
DOI: 10.1101/LM.692407
Abstract: Recent findings reveal qualitative developmental differences in extinction of learned fear. The present study explored potential developmental differences in the role of NMDA in acquisition and extinction. Rats were injected with MK-801 prior to fear conditioning or extinction training. Acquisition was found to be NMDA dependent in both age groups, whereas extinction was found to be NMDA dependent in 23-day-old rats, but NMDA independent in 16-day-old rats. These results illustrate another fundamental developmental difference in extinction as well as a dissociation in the role of NMDA in the acquisition and extinction of fear early in development.
Extinction of a cocaine-taking context that protects against drug-primed reinstatement is dependent on the metabotropic glutamate 5 receptor.
Publisher: Wiley
Date: 09-04-2014
DOI: 10.1111/ADB.12142
Abstract: We investigated the effects of extinguishing action-reward versus context-reward associations on drug-primed reinstatement, and the potential role of the metabotropic glutamate 5 receptor (mGlu5) in these different types of extinction in rats that self-administer cocaine. We observed that daily context extinction (non-reinforced exposures to the cocaine-taking context with retracted levers) was just as effective as daily lever extinction in reducing cocaine-primed reinstatement compared with passive abstinence. Additionally, systemic injections of the mGlu5 negative allosteric modulator MTEP (3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]-pyridine) following each extinction session significantly impaired the ability of context extinction to reduce cocaine-primed reinstatement, without affecting reinstatement after lever extinction or passive abstinence.
Spatial Learning Requires mGlu5 Signalling in the Dorsal Hippocampus.
Publisher: Springer Science and Business Media LLC
Date: 10-05-2015
DOI: 10.1007/S11064-015-1595-0
Abstract: We examined the role of hippoc al metabotropic glutamate receptor 5 (mGlu5) in spatial learning and memory. Although it has been shown that mGlu5 signalling is required for certain forms of learning and memory, its role in spatial learning is unclear since studies using pharmacological or knockout mice models provide inconsistent findings. Additionally, the location in the brain where mGlu5 signalling may modulate such learning is yet to be precisely delineated. We stereotaxically injected rAAV-Cre into the dorsal hippoc us of mGlu5(loxP/loxP) mice to knockdown mGlu5 in that region. We show for the first time that knockdown of mGlu5 in the dorsal hippoc us is sufficient to impair spatial learning in Morris Water Maze. Locomotor activity and memory retrieval were unaffected by the mGlu5 knockdown. Taken together, these findings support a key role for dorsal hippoc al mGlu5 signalling in spatial learning.
Drugs currently in Phase II clinical trials for cocaine addiction
Publisher: Informa Healthcare
Date: 29-04-2014
DOI: 10.1517/13543784.2014.915312
Abstract: There are no FDA-approved pharmacotherapies for treating cocaine addiction thus, developing drugs to treat cocaine dependence is an unmet critical need. Fortunately, there are a number of drugs that are currently in Phase II clinical trial/s. This is due in part to the advances from in vivo imaging in humans which provided a roadmap of the neurochemistry of the cocaine-dependent brain. Most drugs currently in Phase II clinical trials attempt to modulate the disturbed neurochemistry in cocaine dependents to resemble those of healthy in iduals. These predominantly modulate dopamine, serotonin, glutamate, GABA or noradrenaline signalling. This review summarizes the therapeutic potential of each drug as evidenced by clinical and preclinical studies. It also discusses their utility in terms of bioavailability and half-life. Amphetamine salts and topiramate clearly stand out in terms of their potential efficacy in treating cocaine addiction. The efficacy of topiramate was closely associated with regular cognitive-behavioural therapy (CBT), which highlights the importance of a combined effort to promote abstinence and enhance retention via CBT. Cognitive sychological screening appears necessary for a more symptom-based approach with more reasonable outcomes other than abstinence (e.g., improved quality of life) in treating cocaine addiction.
Ontogeny of memory: An update on 40 years of work on infantile amnesia
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.BBR.2015.07.030
Abstract: Given the profound influence that early life experiences can have upon psychosocial functioning later in life, it is intriguing that most adults fail to recall autobiographical events from their early childhood years. Infantile amnesia is the term used to describe this phenomenon of accelerated forgetting during infancy, and it is not unique to humans. Over the years, information garnered from animal studies has provided clues as to the neurobiological basis of infantile amnesia. The purpose of this review is to provide a neurobiological update on what we now know about infantile amnesia since the publication of C bell and Spear's seminal review on the topic more than 40 years ago. We present evidence that infantile amnesia is unlikely to be explained by a unitary theory, with the protracted development of multiple brain regions and neurotransmitter systems important for learning and memory likely to be involved. The recent discovery that exposure to early life stress can alleviate infantile amnesia offers a potential explanation as to how early adversity can so profoundly affect mental health in adulthood, and understanding the neurobiological basis for this early transition may lead to the development of effective therapeutic interventions.
Related Organisations
Florey Institute Of Neuroscience And Mental Health
Location: Australia
Related Funding Activities
Discovery Projects - Grant ID: DP210102672
Start Date: 07-2021
End Date: 06-2024
Amount: $519,615.00
Funder: Australian Research Council
View Funded ActivityDiscovery Early Career Researcher Award - Grant ID: DE120100110
Start Date: 02-2012
End Date: 12-2014
Amount: $375,000.00
Funder: Australian Research Council
View Funded ActivityARC Future Fellowships - Grant ID: FT220100351
Start Date: 06-2023
End Date: 06-2027
Amount: $1,048,536.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP150102496
Start Date: 2015
End Date: 12-2017
Amount: $355,100.00
Funder: Australian Research Council
View Funded Activity