The role of the GABAergic cells of the median raphe region in reinforcement-based learning.

Learning and memory are important in everyday life as well as in pathological conditions. The median raphe region (MRR) contributes to memory formation; however, its precise role and the neurotransmitters involved have yet to be elucidated. To address this issue, we stimulated the MRR neurons of mice by chemogenetic technique and studied them in the operant conditioning and active avoidance tests. The virus carrier infected a variety of neuron types including both GABAergic and glutamatergic ones. Behavior was not influenced by stimulation. We hypothesize that the lack of effect was due to opposing effects exerted via GABAergic and glutamatergic neurons. Therefore, next we used VGAT-Cre mice that allowed the specific manipulation of MRR-GABAergic neurons. The stimulation did not affect behavior in the learning phase of the operant conditioning task, but increased reward preference and total responses when operant contingencies were reversed. The enhanced responsiveness might be a proclivity to impulsive behavior. Stimulation facilitated learning in the active avoidance test but did not affect reversal learning in this paradigm. Our findings suggest that MRR-GABAergic neurons are involved in both learning and reversal learning, but the type of learning that is affected depends on the task.

Anxiety Modulation by Cannabinoids-The Role of Stress Responses and Coping.

Endocannabinoids were implicated in a variety of pathological conditions including anxiety and are considered promising new targets for anxiolytic drug development. The optimism concerning the potentials of this system for anxiolysis is probably justified. However, the complexity of the mechanisms affected by endocannabinoids, and discrepant findings obtained with various experimental approaches makes the interpretation of research results difficult. Here, we review the anxiety-related effects of the three main interventions used to study the endocannabinoid system: pharmacological agents active at endocannabinoid-binding sites present on both the cell membrane and in the cytoplasm, genetic manipulations targeting cannabinoid receptors, and function-enhancers represented by inhibitors of endocannabinoid degradation and transport. Binding-site ligands provide inconsistent findings probably because they activate a multitude of mechanisms concomitantly. More robust findings were obtained with genetic manipulations and particularly with function enhancers, which heighten ongoing endocannabinoid activation rather than affecting all mechanisms indiscriminately. The enhancement of ongoing activity appears to ameliorate stress-induced anxiety without consistent effects on anxiety in general. Limited evidence suggests that this effect is achieved by promoting active coping styles in critical situations. These findings suggest that the functional enhancement of endocannabinoid signaling is a promising drug development target for stress-related anxiety disorders.

The effects of expected and unexpected stress on inappropriate aggression in simulated police interventions.

Here we performed a before-after ABA-design study in police cadets (N = 82) to compare the effects of unexpected (event-triggered) and expected (anticipatory) stressors on aggression. On the first day of the study, participants filled in the Buss-Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale (BIS) and were fitted with heart rate (HR) monitors, which remained attached till the end of the study. On day 2, they were instructed to perform a police intervention in a realistic training environment. The intervention was preceded either by a warning or by a reassuring audio recording that forecasted violent or routine interventions, respectively. Both groups encountered hostile suspects at the intervention site, the behavior of which, however, did not justify the use of force e.g., aggression. The warning resulted in a gradually developing anticipatory stress as shown by HRs. Cadets exposed to the reassuring audio recording showed minimal anticipatory stress but responded to the hostile suspects by an abrupt increase in HRs, which was missing in the warned group. The magnitude of HR responses was similar in the two groups, only their temporal evolution differed. Although aggression showed some associations with BPAQ and BIS scores, the main predictors of behavior were HR changes according to a Multiple Regression analysis. The gradually developing anticipatory stress was associated with low, whereas the abrupt increase in HRs was associated with high aggression. Our findings suggest that the anticipation of a stressful event improves behavioral control whereas an unexpected stress strongly promotes aggression.

Drug regulations and trafficking: Synthetic cannabinoids and cathinones in Hungary.

In principle, new psychoactive substances (NPSs) are produced to circumvent drug regulations. However, the mixed success of regulatory efforts suggests that the dynamics of marketing is incompletely understood. To address this issue, we conducted a comprehensive study on the marketing of all synthetic cannabinoids and cathinones present in Hungary over ten years. Market evaluation was based on drug seizure data and chemical analyses provided by the Hungarian Institute for Forensic Sciences. Over ten years, 18 synthetic cannabinoids and 11 cathinones were identified. Total seizure counts were 22,906 and 10,273, respectively. When new synthetic cannabinoids emerged, seizures increased exponentially, but rapidly declined after their banning. In parallel, new synthetic cannabinoids emerged on the market. The systematic monitoring of local legislation allowed large sales between market introduction and legal control. Cathinones were also marketed in successive waves, but trading intensity was not associated with local regulations. Sales remained low throughout, likely because the risks involved by the temporal mismatch between marketing and legal control. One can hypothesize that marketing was driven by general trends in EU regulations or by measures taken by large countries. Our findings imply the existence of two different strategies for NPS marketing. The choice between the two may depend on multiple factors from the availability of skills required by rapid marketing adjustments to cost/benefit evaluations for various market segments. Studying NPS market strategies in neighboring and distant EU countries may help analyzing and predicting market events.

The effectiveness of extinction training in male rats: Temporal considerations and brain mechanisms.

The extinction of conditioned fear is frequently used in laboratories as a model for human exposure therapy and is crucial for studies of posttraumatic stress disorder (PTSD). However, the efficacy of specific protocols can vary greatly, and the underlying brain mechanisms are not sufficiently clarified. To address this issue, variable starting time (one or twenty-eight days after fear conditioning) and extinction protocols were used, and the efficacy and durability of fear extinction were also studied. Changes in the behavior, stress hormone levels and neuronal activation patterns of stressed rats were analyzed. Conditioned fear was rapidly and efficiently extinguished by all the protocols investigated. However, when these extinction protocols were initiated one day after fear training, conditioned fear relapsed spontaneously four weeks later. In contrast, when extinction trials were started 28 days after conditioning, no relapse occurred. Hormone measurements taken by the end of extinction trials indicated that adrenocorticotropin, but not corticosterone responses reflected behavioral extinction without any sign of relapse. The last extinction training increased the activation of the medial prefrontal cortex and decreased the activation of the central and medial amygdala when extinction began one day after fear conditioning. By contrast, the activation of the basolateral amygdala and the entire hippocampus decreased by the last training session when extinction started 28 days after fear conditioning. Our findings show that extinction training can extinguish remote fear memories more effectively than recent ones, and that the brain mechanisms underlying remote and recent fear memory extinction differ. Laboratory models should also focus on a later time point to increase their translational value.

Aggression, Aggression-Related Psychopathologies and Their Models.

Neural mechanisms of aggression and violence are often studied in the laboratory by means of animal models. A multitude of such models were developed over the last decades, which, however, were rarely if ever compared systematically from a psychopathological perspective. By overviewing the main models, I show here that the classical ones exploited the natural tendency of animals to defend their territory, to fight for social rank, to defend themselves from imminent dangers and to defend their pups. All these forms of aggression are functional and adaptive; consequently, not necessarily appropriate for modeling non-natural states, e.g., aggression-related psychopathologies. A number of more psychopathology-oriented models were also developed over the last two decades, which were based on the etiological factors of aggression-related mental disorders. When animals were exposed to such factors, their aggressiveness suffered durable changes, which were deviant in the meaning that they broke the evolutionarily conserved rules that minimize the dangers associated with aggression. Changes in aggression were associated with a series of dysfunctions that affected other domains of functioning, like with aggression-related disorders where aggression is just one of the symptoms. The comparative overview of such models suggests that while the approach still suffers from a series of deficits, they hold the important potential of extending our knowledge on aggression control over the pathological domain of this behavior.

Risk Matrix for Violent Radicalization: A Machine Learning Approach.

Hypothesis-driven approaches identified important characteristics that differentiate violent from non-violent radicals. However, they produced a mosaic of explanations as they investigated a restricted number of preselected variables. Here we analyzed without a priory assumption all the variables of the "Profiles of Individual Radicalization in the United States" database by a machine learning approach. Out of the 79 variables considered, 19 proved critical, and predicted the emergence of violence with an accuracy of 86.3%. Typically, violent extremists came from criminal but not radical backgrounds and were radicalized in late stages of their life. They were followers in terrorist groups, sought training, and were radicalized by social media. They belonged to low social strata and had problematic social relations. By contrast, non-violent but still criminal extremists were characterized by a family tradition of radicalism without having criminal backgrounds, belonged to higher social strata, were leaders in terrorist organizations, and backed terrorism by supporting activities. Violence was also promoted by anti-gay, Sunni Islam and Far Right, and hindered by Far Left, Anti-abortion, Animal Rights and Environment ideologies. Critical characteristics were used to elaborate a risk-matrix, which may be used to predict violence risk at individual level.

Glucocorticoids and Aggression: A Tripartite Interaction.

The effects of glucocorticoids on aggression can be conceptualized based on its mechanisms of action. These hormones can affect cell function non-genomically within minutes, primarily by affecting the cell membrane. Overall, such effects are activating and promote both metabolic preparations for the fight and aggressive behavior per se. Chronic increases in glucocorticoids activate genomic mechanisms and are depressing overall, including the inhibition of aggressive behavior. Finally, excessive stressors trigger epigenetic phenomena that have a large impact on brain programming and may also induce the reprogramming of neural functions. These induce qualitative changes in aggression that are deemed abnormal in animals, and psychopathological and criminal in humans. This review aims at deciphering the roles of glucocorticoids in aggression control by taking in view the three mechanisms of action often categorized as acute, chronic, and toxic stress based on the duration and the consequences of the stress response. It is argued that the tripartite way of influencing aggression can be recognized in all three animal, psychopathological, and criminal aggression and constitute a framework of mechanisms by which aggressive behavior adapts to short-term and log-term changes in the environment.

Rescue of Vasopressin Synthesis in Magnocellular Neurons of the Supraoptic Nucleus Normalises Acute Stress-Induced Adrenocorticotropin Secretion and Unmasks an Effect on Social Behaviour in Male Vasopressin-Deficient Brattleboro Rats.

The relevance of vasopressin (AVP) of magnocellular origin to the regulation of the endocrine stress axis and related behaviour is still under discussion. We aimed to obtain deeper insight into this process. To rescue magnocellular AVP synthesis, a vasopressin-containing adeno-associated virus vector (AVP-AAV) was injected into the supraoptic nucleus (SON) of AVP-deficient Brattleboro rats (di/di). We compared +/+, di/di, and AVP-AAV treated di/di male rats. The AVP-AAV treatment rescued the AVP synthesis in the SON both morphologically and functionally. It also rescued the peak of adrenocorticotropin release triggered by immune and metabolic challenges without affecting corticosterone levels. The elevated corticotropin-releasing hormone receptor 1 mRNA levels in the anterior pituitary of di/di-rats were diminished by the AVP-AAV-treatment. The altered c-Fos synthesis in di/di-rats in response to a metabolic stressor was normalised by AVP-AAV in both the SON and medial amygdala (MeA), but not in the central and basolateral amygdala or lateral hypothalamus. In vitro electrophysiological recordings showed an AVP-induced inhibition of MeA neurons that was prevented by picrotoxin administration, supporting the possible regulatory role of AVP originating in the SON. A memory deficit in the novel object recognition test seen in di/di animals remained unaffected by AVP-AAV treatment. Interestingly, although di/di rats show intact social investigation and aggression, the SON AVP-AAV treatment resulted in an alteration of these social behaviours. AVP released from the magnocellular SON neurons may stimulate adrenocorticotropin secretion in response to defined stressors and might participate in the fine-tuning of social behaviour with a possible contribution from the MeA.

Double-blind placebo controlled trial of the anxiolytic effects of a standardized Echinacea extract.

Earlier studies suggested that specific Echinacea preparations might decrease anxiety. To further study the issue, we performed a double blind, placebo controlled trial with a standardized Echinacea angustifolia root extract. Participants were volunteers scoring above 45 points on the state or on the trait subscale of the State Trait Anxiety Inventory (STAI). They were treated with 40 mg Echinacea or with placebo tablets twice daily for 7 days followed by a 3 week-long washout period. Participants were also administered the Beck Depression Inventory (BDI) and the Perceived Stress Scale (PSS). In the Echinacea group, state anxiety scores decreased by approximately 11 points by the end of the treatment period, whereas the decrease was around 3-points in the placebo group (p< 0.01). The effect maintained over the washout period. The difference from placebo was significant from the 7th day of treatment throughout. Changes were less robust with trait anxiety scores, but the preparation performed better than placebo in patients with high baseline anxiety. Neither BDI nor PSS scores were affected by the treatments. Adverse effects were rare and mild, and all were observed in the placebo group. These findings suggest that particular Echinacea preparations have significant beneficial effects on anxiety in humans.

Consequences of VGluT3 deficiency on learning and memory in mice.

The aim of the present study was to test the hypothesis that vesicular glutamate transporter 3 (VGluT3) deficiency is associated with cognitive impairments. Male VGluT3 knockout (KO) and wild type (WT) mice were exposed to a behavioral test battery covering paradigms based on spontaneous exploratory behavior and reinforcement-based learning tests. Reversal learning was examined to test the cognitive flexibility. The VGluT3 KO mice clearly exhibited the ability to learn. The social recognition memory of KO mice was intact. The y-maze test revealed weaker working memory of VGluT3 KO mice. No significant learning impairments were noticed in operant conditioning or holeboard discrimination paradigm. In avoidance-based learning tests (Morris water maze and active avoidance), KO mice exhibited slightly slower learning process compared to WT mice, but not a complete learning impairment. In tests based on simple associations (operant conditioning, avoidance learning) an attenuation of cognitive flexibility was observed in KO mice. In conclusion, knocking out VGluT3 results in mild disturbances in working memory and learning flexibility. Apparently, this glutamate transporter is not a major player in learning and memory formation in general. Based on previous characteristics of VGluT3 KO mice we would have expected a stronger deficit. The observed hypolocomotion did not contribute to the mild cognitive disturbances herein reported, either.

Endocannabinoid interactions in the regulation of acquisition of contextual conditioned fear.

Endocannabinoids (eCBs) anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were shown to be involved in the basis of trauma-induced behavioral changes, particularly contextual conditioned fear, however, their ligand-specific effects and possible interactions are poorly understood. Here we assessed specific eCB effects and interactions on acquisition of contextual conditioned fear employing electric footshocks in a rat model. We selectively increased eCB levels by pharmacological blockade of the degrading enzymes of AEA by URB597 and 2-AG by JZL184 before traumatization either systemically or locally in relevant brain areas, the prelimbic cortex (PrL), ventral hippocampus (vHC) and basolateral amygdala (BLA). Following traumatization, a series of contextual reminders were conducted during which conditioned fear was assessed. While systemic URB597-treatment during traumatization only slightly enhanced the acquisition of contextual conditioned fear, administration of the compound in the PrL and vHC led to the acquisition of stable, lasting conditioned fear, resistant to extinction. These effects of URB597 were blocked by simultaneous administration of JZL184. Similar treatment effects did not occur in the BLA. Treatment effects were not secondary to alterations in locomotor activity or nociception. Our findings suggest that AEA and 2-AG functionally interact in the regulation of acquisition of contextual conditioned fear. AEA signaling in the PrL and vHC is a crucial promoter of fear acquisition while 2-AG potentially modulates this effect. The lack of eCB effects in the BLA suggests functional specificity of eCBs at distinct brain sites.

The swimming plus-maze test: a novel high-throughput model for assessment of anxiety-related behaviour in larval and juvenile zebrafish (Danio rerio).

Larval zebrafish (Danio rerio) has the potential to supplement rodent models due to the availability of resource-efficient, high-throughput screening and high-resolution imaging techniques. Although behavioural models are available in larvae, only a few can be employed to assess anxiety. Here we present the swimming plus-maze (SPM) test paradigm, a tool to assess anxiety-related avoidance of shallow water bodies in early developmental stages. The "+" shaped apparatus consists of arms of different depth, representing different levels of aversiveness similarly to the rodent elevated plus-maze. The paradigm was validated (i) in larval and juvenile zebrafish, (ii) after administration of compounds affecting anxiety and (iii) in differentially aversive experimental conditions. Furthermore, we compared the SPM with conventional "anxiety tests" of zebrafish to identify their shared characteristics. We have clarified that the preference of deeper arms is ontogenetically conserved and can be abolished by anxiolytic or enhanced by anxiogenic agents, respectively. The behavioural readout is insensitive to environmental aversiveness and is unrelated to behaviours assessed by conventional tests involving young zebrafish. Taken together, we have developed a sensitive high-throughput test allowing the assessment of anxiety-related responses of zebrafish regardless of developmental stage, granting the opportunity to combine larva-based state-of-the-art methods with detailed behavioral analysis.

Differential Roles of the Two Raphe Nuclei in Amiable Social Behavior and Aggression - An Optogenetic Study.

Serotonergic mechanisms hosted by raphe nuclei have important roles in affiliative and agonistic behaviors but the separate roles of the two nuclei are poorly understood. Here we studied the roles of the dorsal (DR) and median raphe region (MRR) in aggression by optogenetically stimulating the two nuclei. Mice received three 3 min-long stimulations, which were separated by non-stimulation periods of 3 min. The stimulation of the MRR decreased aggression in a phasic-like manner. Effects were rapidly expressed during stimulations, and vanished similarly fast when stimulations were halted. No carryover effects were observed in the subsequent three trials performed at 2-day intervals. No effects on social behaviors were observed. By contrast, DR stimulation rapidly and tonically promoted social behaviors: effects were present during both the stimulation and non-stimulation periods of intermittent stimulations. Aggressive behaviors were marginally diminished by acute DR stimulations, but repeated stimulations administered over 8 days considerably decreased aggression even in the absence of concurrent stimulations, indicating the emergence of carryover effects. No such effects were observed in the case of social behaviors. We also investigated stimulation-induced neurotransmitter release in the prefrontal cortex, a major site of aggression control. MRR stimulation rapidly but transiently increased serotonin release, and induced a lasting increase in glutamate levels. DR stimulation had no effect on glutamate, but elicited a lasting increase of serotonin release. Prefrontal serotonin levels remained elevated for at least 2 h subsequent to DR stimulations. The stimulation of both nuclei increased GABA release rapidly and transiently. Thus, differential behavioral effects of the two raphe nuclei were associated with differences in their neurotransmission profiles. These findings reveal a surprisingly strong behavioral task division between the two raphe nuclei, which was associated with a nucleus-specific neurotransmitter release in the prefrontal cortex.

The Role of the Lateral Hypothalamus in Violent Intraspecific Aggression-The Glucocorticoid Deficit Hypothesis.

This review argues for a central role of the lateral hypothalamus in those deviant forms of aggression, which result from chronic glucocorticoid deficiency. Currently, this nucleus is considered a key region of the mechanisms that control predatory aggression. However, recent findings demonstrate that it is strongly activated by aggression in subjects with a chronically downregulated hypothalamus-pituitary-adrenocortical (HPA) axis; moreover, this activation is causally involved in the emergence of violent aggression. The review has two parts. In the first part, we review human findings demonstrating that under certain conditions, strong stressors downregulate the HPA-axis on the long run, and that the resulting glucocorticoid deficiency is associated with violent aggression including aggressive delinquency and aggression-related psychopathologies. The second part addresses neural mechanisms in animals. We show that the experimental downregulation of HPA-axis function elicits violent aggression in rodents, and the activation of the brain circuitry that originally subserves predatory aggression accompanies this change. The lateral hypothalamus is not only an integral part of this circuitry, but can elicit deviant and violent forms of aggression. Finally, we formulate a hypothesis on the pathway that connects unfavorable social conditions to violent aggression via the neural circuitry that includes the lateral hypothalamus.

Task Division within the Prefrontal Cortex: Distinct Neuron Populations Selectively Control Different Aspects of Aggressive Behavior via the Hypothalamus.

An important question in behavioral neurobiology is how particular neuron populations and pathways mediate the overall roles of brain structures. Here we investigated this issue by studying the medial prefrontal cortex (mPFC), an established locus of inhibitory control of aggression. We established in male rats that dominantly distinct mPFC neuron populations project to and produce dense fiber networks with glutamate release sites in the mediobasal hypothalamus (MBH) and lateral hypothalamus (LH; i.e., two executory centers of species-specific and violent bites, respectively). Optogenetic stimulation of mPFC terminals in MBH distinctively increased bite counts in resident/intruder conflicts, whereas the stimulation of similar terminals in LH specifically resulted in violent bites. No other behaviors were affected by stimulations. These findings show that the mPFC controls aggressiveness by behaviorally dedicated neuron populations and pathways, the roles of which may be opposite to those observed in experiments where the role of the whole mPFC (or of its major parts) has been investigated. Overall, our findings suggest that the mPFC organizes into working units that fulfill specific aspects of its wide-ranging roles.SIGNIFICANCE STATEMENT Aggression control is associated with many cognitive and emotional aspects processed by the prefrontal cortex (PFC). However, how the prefrontal cortex influences quantitative and qualitative aspects of aggressive behavior remains unclear. We demonstrated that dominantly distinct PFC neuron populations project to the mediobasal hypothalamus (MBH) and the lateral hypothalamus (LH; i.e., two executory centers of species-specific and violent bites, respectively). Stimulation of mPFC fibers in MBH distinctively increased bite counts during fighting, whereas stimulation of similar terminals in LH specifically resulted in violent bites. Overall, our results suggest a direct prefrontal control over the hypothalamus, which is involved in the modulation of quantitative and qualitative aspects of aggressive behavior through distinct prefrontohypothalamic projections.

Enhanced innate fear and altered stress axis regulation in VGluT3 knockout mice.

Glutamatergic neurons, characterized by vesicular glutamate transporters (VGluT1-3) provide the main excitation in the brain. Their disturbances have been linked to various brain disorders, which could be also modeled by the contextual fear test in rodents. We aimed to characterize the participation of VGluT3 in the development of contextual fear through its contribution to hypothalamic-pituitary-adrenocortical axis (HPA) regulation using knockout (KO) mice. Contextual fear conditioning was induced by foot shock and mice were examined 1 and 7 d later in the same environment comparing wild type with KO. Foot shock increased the immobility time without context specificity. Additionally, foot shock reduced open arm time in the elevated plus maze (EPM) test, and distance traveled in the open field (OF) test, representing the generalization of fear. Moreover, KO mice spent more time with freezing during the contextual fear test, less time in the open arm of the EPM, and traveled a smaller distance in the OF, with less entries into the central area. However, there was no foot shock and genotype interaction suggesting that VGluT3 does not influence the fear conditioning, rather determines anxiety-like characteristic of the mice. The resting hypothalamic CRH mRNA was higher in KO mice with reduced stressor-induced corticosterone elevations. Immunohistochemistry revealed the presence of VGluT3 positive fibers in the paraventricular nucleus of hypothalamus, but not on the hypophysis. As a summary, we confirmed the involvement of VGluT3 in innate fear, but not in the development of fear memory and generalization, with a significant contribution to HPA alterations. Highlights VGluT3 KO mice show innate fear without significant influence on fear memory and generalization. A putative background is the higher resting CRH mRNA level in their PVN and reduced stress-reactivity.

The role of central and medial amygdala in normal and abnormal aggression: A review of classical approaches.

The involvement of the amygdala in aggression is supported by overwhelming evidence. Frequently, however, the amygdala is studied as a whole, despite its complex internal organization. To reveal the role of various subdivisions, here we review the involvement of the central and medial amygdala in male rivalry aggression, maternal aggression, predatory aggression, and models of abnormal aggression where violent behavior is associated with increased or decreased arousal. We conclude that: (1) rivalry aggression is controlled by the medial amygdala; (2) predatory aggression is controlled by the central amygdala; (3) hypoarousal-associated violent aggression recruits both nuclei, (4) a specific upregulation of the medial amygdala was observed in hyperarousal-driven aggression. These patterns of amygdala activation were used to build four alternative models of the aggression circuitry, each being specific to particular forms of aggression. The separate study of the roles of amygdala subdivisions may not only improve our understanding of aggressive behavior, but also the differential control of aggression and violent behaviors of various types, including those associated with various psychopathologies.

Contribution of Vesicular Glutamate Transporters to Stress Response and Related Psychopathologies: Studies in VGluT3 Knockout Mice.

Maintenance of the homeostasis in a constantly changing environment is a fundamental process of life. Disturbances of the homeostatic balance is defined as stress response and is induced by wide variety of challenges called stressors. Being the main excitatory neurotransmitter of the central nervous system glutamate is important in the adaptation process of stress regulating both the catecholaminergic system and the hypothalamic-pituitary-adrenocortical axis. Data are accumulating about the role of different glutamatergic receptors at all levels of these axes, but little is known about the contribution of different vesicular glutamate transporters (VGluT1-3) characterizing the glutamatergic neurons. Here we summarize basic knowledge about VGluTs, their role in physiological regulation of stress adaptation, as well as their contribution to stress-related psychopathology. Most of our knowledge comes from the VGluT3 knockout mice, as VGluT1 and 2 knockouts are not viable. VGluT3 was discovered later than, and is not as widespread as the VGluT1 and 2. It may co-localize with other transmitters, and participate in retrograde signaling; as such its role might be unique. Previous reports using VGluT3 knockout mice showed enhanced anxiety and innate fear compared to wild type. Moreover, these knockout animals had enhanced resting corticotropin-releasing hormone mRNA levels in the hypothalamus and disturbed glucocorticoid stress responses. In conclusion, VGluT3 participates in stress adaptation regulation. The neuroendocrine changes observed in VGluT3 knockout mice may contribute to their anxious, fearful phenotype.

Social Learning Requires Plasticity Enhanced by Fluoxetine Through Prefrontal Bdnf-TrkB Signaling to Limit Aggression Induced by Post-Weaning Social Isolation.

Escalated or abnormal aggression induced by early adverse experiences is a growing issue of social concern and urges the development of effective treatment strategies. Here we report that synergistic interactions between psychosocial and biological factors specifically ameliorate escalated aggression induced by early adverse experiences. Rats reared in isolation from weaning until early adulthood showed abnormal forms of aggression and social deficits that were temporarily ameliorated by re-socialization, but aggression again escalated in a novel environment. We demonstrate that when re-socialization was combined with the antidepressant fluoxetine, which has been shown to reactivate juvenile-like state of plasticity, escalated aggression was greatly attenuated, while neither treatment alone was effective. Early isolation induced a permanent, re-socialization-resistant reduction in Bdnf expression in the amygdala and the infralimbic cortex. Only the combined treatment of fluoxetine and re-socialization was able to recover Bdnf expression via epigenetic regulation. Moreover, the behavior improvement after the combined treatment was dependent on TrkB activity. Combined treatment specifically strengthened the input from the ventral hippocampus to the mPFC, suggesting that this pathway is an important mediator of the beneficial behavioral effects of the combined psychosocial and pharmacological treatment of abnormal aggression. Our findings suggest that synergy between pharmacological induction of plasticity and psychosocial rehabilitation could enhance the efficacy of therapies for pathological aggression.