Effects of the designer drug 4-methylamphetamine on core temperature and serotonin levels in the striatum and hippocampus of rats.

New psychoactive substances (NPS) are typically synthesized in clandestine laboratories in an attempt to chemically modify already federally regulated drugs in an effort to circumvent the law. Drugs derived from a phenethylamine pharmacophore, such as 4-chloroamphetamine and 3,4-methylenedioxymethamphetamine (MDMA), reliably induce thermogenesis and serotonergic deficits in the striatum and hippocampus of rodents. 4-methylamphetamine (4-MA), a relative newcomer to the NPS scene, was originally investigated in the mid-1900 s as a potential anorexigenic agent. With its phenethylamine pharmacophore, 4-MA was hypothesized to produce similar toxicological alterations as its chemical analogs. In the present study, three doses (1.0, 2.5, and 5.0 mg/kg, ip.) of 4-MA were administered to rats twice daily for two days. Core temperature data were calculated and analyzed as temperature area under the curve (TAUC). On the second day of dosing, a hypothermic response to 4-MA (2.5 and 5.0 mg/kg) was noted between 0.5 and 2.0 h post-treatment. Only the highest dose of 4-MA decreased body weight on the second day of treatment and maintained this reduction in weight for seven days after treatment ceased. None of the doses of 4-MA evaluated significantly altered serotonin levels in the hippocampus or striatum seven days after final treatment. The present findings demonstrate that the 4-methyl substitution to amphetamine generates a pharmacological and toxicological profile that differs from other similar phenethylamine analogs.

Heterotypic Stressors Unmask Behavioral Influences of PMAT Deficiency in Mice.

Certain life stressors having enduring physiological and behavioral consequences, in part by eliciting dramatic signaling shifts in monoamine neurotransmitters. High monoamine levels can overwhelm selective transporters like the serotonin transporter. This is when polyspecific transporters like plasma membrane monoamine transporter (PMAT, Slc29a4) are hypothesized to contribute most to monoaminergic signaling regulation. Here, we employed two distinct counterbalanced stressors-fear conditioning and swim stress-in mice to systematically determine how reductions in PMAT function affect heterotypic stressor responsivity. We hypothesized that male heterozygotes would exhibit augmented stressor responses relative to female heterozygotes. Decreased PMAT function enhanced context fear expression, an effect unexpectedly obscured by a sham stress condition. Impaired cued fear extinction retention and enhanced context fear expression in males were conversely unmasked by a sham swim condition. Abrogated corticosterone levels in male heterozygotes that underwent swim stress after context fear conditioning did not map onto any measured behaviors. In sum, male heterozygous mouse fear behaviors proved malleable in response to preceding stressor or sham stress exposure. Combined, these data indicate that reduced male PMAT function elicits a form of stress-responsive plasticity. Future studies should assess how PMAT is differentially affected across sexes and identify downstream consequences of the stress-shifted corticosterone dynamics.

Heterotypic stressors unmask behavioral influences of PMAT deficiency in mice.

Certain life stressors having enduring physiological and behavioral consequences, in part by eliciting dramatic signaling shifts in monoamine neurotransmitters. High monoamine levels can overwhelm selective transporters like the serotonin transporter. This is when polyspecific transporters like plasma membrane monoamine transporter (PMAT, Slc29a4) are hypothesized to contribute most to monoaminergic signaling regulation. Here, we employed two distinct counterbalanced stressors - fear conditioning, and swim stress - in mice to systematically determine how reductions in PMAT function affect heterotypic stressor responsivity. We hypothesized male heterozygotes would exhibit augmented stressor responses relative to female heterozygotes. Decreased PMAT function enhanced context fear expression, an effect unexpectedly obscured by a sham stress condition. Impaired cued fear extinction retention and enhanced context fear expression in males were conversely unmasked by a sham swim condition. Abrogated corticosterone levels in male heterozygotes that underwent swim stress after context fear conditioning did not map on to any measured behaviors. In sum, male heterozygous mouse fear behaviors proved malleable in response to preceding stressor or sham stress exposure. Combined, these data indicate reduced male PMAT function elicits a form of stress-responsive plasticity. Future studies should assess how PMAT is differentially affected across sexes and identify downstream consequences of the stress-shifted corticosterone dynamics.

Generalization of contextual fear is sex-specifically affected by high salt intake.

A hallmark symptom of many anxiety disorders, and multiple neuropsychiatric disorders more broadly, is generalization of fearful responses to non-fearful stimuli. Anxiety disorders are often comorbid with cardiovascular diseases. One established, and modifiable, risk factor for cardiovascular diseases is salt intake. Yet, investigations into how excess salt consumption affects anxiety-relevant behaviors remains little explored. Moreover, no studies have yet assessed how high salt intake influences generalization of fear. Here, we used adult C57BL/6J mice of both sexes to evaluate the influence of two or six weeks of high salt consumption (4.0% NaCl), compared to controls (0.4% NaCl), on contextual fear acquisition, expression, and generalization. Further, we measured osmotic and physiological stress by quantifying serum osmolality and corticosterone levels, respectively. Consuming excess salt did not influence contextual fear acquisition nor discrimination between the context used for training and a novel, neutral context when training occurred 48 prior to testing. However, when a four week delay between training and testing was employed to induce natural fear generalization processes, we found that high salt intake selectively increases contextual fear generalization in females, but the same diet reduces contextual fear generalization in males. These sex-specific effects were independent of any changes in serum osmolality nor corticosterone levels, suggesting the behavioral shifts are a consequence of more subtle, neurophysiologic changes. This is the first evidence of salt consumption influencing contextual fear generalization, and adds information about sex-specific effects of salt that are largely missing from current literature.

Summarizing studies using constitutive genetic deficiency to investigate behavioural influences of uptake 2 monoamine transporters.

Burgeoning literature demonstrates that monoamine transporters with high transport capacity but lower substrate affinity (i.e., uptake 2) contribute meaningfully to regulation of monoamine neurotransmitter signalling. However, studying behavioural influences of uptake 2 is hindered by an absence of selective inhibitors largely free of off-target, confounding effects. This contrasts with study of monoamine transporters with low transport capacity but high substrate affinity (i.e., uptake 1), for which there are many reasonably selective inhibitors. To circumvent this dearth of pharmacological tools for studying uptake 2, researchers have instead employed mice with constitutive genetic deficiency in three separate transporters. By studying baseline behavioural shifts, plus behavioural responses to environmental and pharmacological manipulations-the latter primarily targeting uptake 1-investigators have been creatively characterizing the behavioural, and often sex-specific, influences of uptake 2. This non-systematic mini review summarizes current uptake 2 behaviour literature, highlighting emphases on stress responsivity in organic cation transporter 2 (OCT2) work, psychostimulant responsivity in OCT3 and plasma membrane monoamine transporter (PMAT) investigations, and antidepressant responsivity in all three. Collectively, this small but growing body of work reiterates the necessity for development of selective uptake 2-inhibiting drugs, with reviewed studies suggesting that these might advance personalized treatment approaches.

Anxiety and stress over COVID-19 pandemic associated with increased eating.

Objective: Stressful experiences can dramatically affect eating. The relatively sudden, global emergence of the COVID-19 pandemic served as a massive stressor to virtually all people, regardless of infection status. This study hypothesized that actual and perceived stressors from the onset of the COVID-19 pandemic, in the categories of recurring disruptions, environmental threat, and social isolation would be positively associated with increased self-reported eating in the United States. Methods: Over 1100 English-fluent adults (52.8% women) living in the United States were recruited for a cross-sectional online survey about eating, COVID-19 consequences, and stress experiences. Linear regressions examined associations between perceived stress on five eating measures, and individual differences in personal/work situations, perceptions, and adverse experiences during the pandemic. Results: Anxiety, worry, and stress over, rather than direct consequences of, COVID-19 were most consistently associated with self-reported increased eating. Largely, these fell into the stressor categories of environmental threat and social isolation, not recurring disruptions. Body mass index and current self-reported eating pathology symptoms were also consistently associated with these outcomes. Conclusions: These correlational findings suggest specific stressors have pronounced influences on eating behavior of US adults. Remotely deliverable stress mitigation strategies should be explored to attenuate increased eating.

Uncovering Functional Contributions of PMAT (Slc29a4) to Monoamine Clearance Using Pharmacobehavioral Tools.

Plasma membrane monoamine transporter (PMAT, Slc29a4) transports monoamine neurotransmitters, including dopamine and serotonin, faster than more studied monoamine transporters, e.g., dopamine transporter (DAT), or serotonin transporter (SERT), but with ~400-600-fold less affinity. A considerable challenge in understanding PMAT's monoamine clearance contributions is that no current drugs selectively inhibit PMAT. To advance knowledge about PMAT's monoamine uptake role, and to circumvent this present challenge, we investigated how drugs that selectively block DAT/SERT influence behavioral readouts in PMAT wildtype, heterozygote, and knockout mice of both sexes. Drugs typically used as antidepressants (escitalopram, bupropion) were administered acutely for readouts in tail suspension and locomotor tests. Drugs with psychostimulant properties (cocaine, D-amphetamine) were administered repeatedly to assess initial locomotor responses plus psychostimulant-induced locomotor sensitization. Though we hypothesized that PMAT-deficient mice would exhibit augmented responses to antidepressant and psychostimulant drugs due to constitutively attenuated monoamine uptake, we instead observed sex-selective responses to antidepressant drugs in opposing directions, and subtle sex-specific reductions in psychostimulant-induced locomotor sensitization. These results suggest that PMAT functions differently across sexes, and support hypotheses that PMAT's monoamine clearance contribution emerges when frontline transporters (e.g., DAT, SERT) are absent, saturated, and/or blocked. Thus, known human polymorphisms that reduce PMAT function could be worth investigating as contributors to varied antidepressant and psychostimulant responses.

DRD4 polymorphism associated with greater positive affect in response to negative and neutral social stimuli.

Despite the robustness of DRD4 polymorphism associations with brain-based behavioral characteristics in candidate gene research, investigations have minimally explored associations between these polymorphisms and emotional responses. In particular, the prevalent single nucleotide polymorphism (SNP) -521C/T (rs1800955) in the promoter region of DRD4 remains unexplored relative to emotions. Here, two independent samples were evaluated using different emotion elicitation tasks involving social stimuli: Study 1 (N = 120) evoked positive and negative emotional responses to validated film clips; Study 2 (N = 122) utilized Cyberball to simulate social rejection and acceptance. Across studies, C/C individuals self-reported higher mean positive affect scores using Likert scales versus T carrier individuals, selectively when presented with neutral or negative (but not positive) social stimuli. The consistent findings across these two studies supports a functional consequence of this DRD4 SNP on emotion processing during changing social contexts. Continued investigation will help clarify if a C/C genotype enhances positive emotions under negative circumstances, or if the presence of the T allele reduces positive emotions, and how rs1800955 behavioral associations might generalize across different demographics. Future studies could also reveal if this SNP interacts with other changing environmental conditions to affect emotional responses, such as social limitations during the COVID-19 pandemic.

Salt as a non-caloric behavioral modifier: A review of evidence from pre-clinical studies.

Though excess salt intake is well-accepted as a dietary risk factor for cardiovascular diseases, relatively little has been explored about how it impacts behavior, despite the ubiquity of salt in modern diets. Given the challenges of manipulating salt intake in humans, non-human animals provide a more tractable means for evaluating behavioral sequelae of high salt. By describing what is known about the impact of elevated salt on behavior, this review highlights how underexplored salt's behavioral effects are. Increased salt consumption in adulthood does not affect spontaneous anxiety-related behaviors or locomotor activity, nor acquisition of maze or fear tasks, but does impede expression of spatial/navigational and fear memory. Nest building is reduced by heightened salt in adults, and stress responsivity is augmented. When excess salt exposure occurs during development, and/or to parents, offspring locomotion is increased, and both spatial memory expression and social investigation are attenuated. The largely consistent findings reviewed here indicate expanded study of salt's effects will likely uncover broader behavioral implications, particularly in the scarcely studied female sex.

Age- and Sex-Specific Plasticity in Dopamine Transporter Function Revealed by Food Restriction and Exercise in a Rat Activity-Based Anorexia Paradigm.

Eating disorders such as anorexia typically emerge during adolescence, are characterized by engagement in compulsive and detrimental behaviors, and are often comorbid with neuropsychiatric disorders and drug abuse. No effective treatments exist. Moreover, anorexia lacks adolescent animal models, contributing to a poor understanding of underlying age-specific neurophysiological disruptions. To evaluate the contribution of dopaminergic signaling to the emergence of anorexia-related behaviors during the vulnerable adolescent period, we applied an established adult activity-based anorexia (ABA) paradigm (food restriction plus unlimited exercise access for 4 to 5 days) to adult and adolescent rats of both sexes. At the end of the paradigm, measures of plasma volume, blood hormone levels, dopamine transporter (DAT) expression and function, acute cocaine-induced locomotion, and brain water weight were taken. Adolescents were dramatically more affected by the ABA paradigm than adults in all measures. In vivo chronoamperometry and cocaine locomotor responses revealed sex-specific changes in adolescent DAT function after ABA that were independent of DAT expression differences. Hematocrit, insulin, ghrelin, and corticosterone levels did not resemble shifts typically observed in patients with anorexia, though decreases in leptin levels aligned with human reports. These findings are the first to suggest that food restriction in conjunction with excessive exercise sex-dependently and age-specifically modulate DAT functional plasticity during adolescence. The adolescent vulnerability to this relatively short manipulation, combined with blood measures, evidence need for an optimized age-appropriate ABA paradigm with greater face and predictive validity for the study of the pathophysiology and treatment of anorexia. SIGNIFICANCE STATEMENT: Adolescent rats exhibit a distinctive, sex-specific plasticity in dopamine transporter function and cocaine response after food restriction and exercise access; this plasticity is both absent in adults and not attributable to changes in dopamine transporter expression levels. These novel findings may help explain sex differences in vulnerability to eating disorders and drug abuse during adolescence.

Neuroinflammation Contributes to High Salt Intake-Augmented Neuronal Activation and Active Coping Responses to Acute Stress.

High dietary salt intake increases risk of stress-related neuropsychiatric disorders. Here, we explored the contribution of high dietary salt intake-induced neuroinflammation in key stress-responsive brain regions, the hypothalamic paraventricular nucleus and basolateral amygdala, in promoting exaggerated neuronal activation and coping behaviors in response to acute psychogenic stress. Mice that underwent high dietary salt intake exhibited increased active stress coping behaviors during and after an acute swim stress, and these were reduced by concurrent administration of minocycline, an inhibitor of microglial activation, without affecting body fluid hyperosmolality caused by high dietary salt intake. Moreover, minocycline attenuated high dietary salt intake-induced increases of paraventricular nucleus tumor necrosis factor-α, activated microglia (ionized calcium-binding adaptor molecule 1), and acute swim stress-induced neuronal activation (c-Fos). In the basolateral amygdala, similar effects were observed on ionized calcium-binding adaptor molecule 1+ and c-Fos+ counts, but not tumor necrosis factor-α levels. These data indicate that high dietary salt intake promotes neuroinflammation, increasing recruitment of neurons in key stress-associated brain regions and augmenting behavioral hyper-responsivity to acute psychological stress.

High Salt Intake Lowers Behavioral Inhibition.

Stress-related neuropsychiatric (e.g., anxiety, depression) and cardiovascular diseases are frequently comorbid, though discerning the directionality of their association has been challenging. One of the most controllable risk factors for cardiovascular disease is salt intake. Though high salt intake is implicated in neuropsychiatric diseases, its direct neurobehavioral effects have seldom been explored. We reported that elevated salt intake in mice augments neuroinflammation, particularly after an acute stressor. Here, we explored how high salt consumption affected behavioral responses of mice to mildly arousing environmental and social tests, then assessed levels of the stress-related hormone corticosterone. Unexpectedly, anxiety-related behaviors in the elevated plus maze, open field, and marble burying test were unaffected by increased salt intake. However, nest building was diminished in mice consuming high salt, and voluntary social interaction was elevated, suggesting reduced engagement in ethologically-relevant behaviors that promote survival by attenuating threat exposure. Moreover, we observed significant positive correlations between social preference and subsequent corticosterone only in mice consuming increased salt, as well as negative correlations between open arm exploration in the elevated plus maze and corticosterone selectively in mice in the highest salt condition. Thus, heightened salt consumption reduces behavioral inhibition under relatively low-threat conditions, and enhances circulating corticosterone proportional to specific behavioral shifts. Considering the adverse health consequences of high salt intake, combined with evidence that increased salt consumption impairs inhibition of context-inappropriate behaviors, we suggest that prolonged high salt intake likely promulgates maladaptive behavioral and cardiovascular responses to perceived stressors that may explain some of the prevalent comorbidity between cardiovascular and neuropsychiatric diseases.

Extreme enhancement or depletion of serotonin transporter function and serotonin availability in autism spectrum disorder.

A variety of human and animal studies support the hypothesis that serotonin (5-hydroxytryptamine or 5-HT) system dysfunction is a contributing factor to the development of autism in some patients. However, many questions remain about how developmental manipulation of various components that influence 5-HT signaling (5-HT synthesis, transport, metabolism) persistently impair social behaviors. This review will summarize key aspects of central 5-HT function important for normal brain development, and review evidence implicating perinatal disruptions in 5-HT signaling in the pathophysiology of autism spectrum disorder. We discuss the importance, and relative dearth, of studies that explore the possible correlation to autism in the interactions between important intrinsic and extrinsic factors that may disrupt 5-HT homeostasis during development. In particular, we focus on exposure to 5-HT transport altering mechanisms such as selective serotonin-reuptake inhibitors or genetic polymorphisms in primary or auxiliary transporters of 5-HT, and how they relate to neurological stores of serotonin and its precursors. A deeper understanding of the many mechanisms by which 5-HT signaling can be disrupted, alone and in concert, may contribute to an improved understanding of the etiologies and heterogeneous nature of this disorder. We postulate that extreme bidirectional perturbations of these factors during development likely compound or synergize to facilitate enduring neurochemical changes resulting in insufficient or excessive 5-HT signaling, that could underlie the persistent behavioral characteristics of autism spectrum disorder.

Basolateral amygdala Thy1-expressing neurons facilitate the inhibition of contextual fear during consolidation, reconsolidation, and extinction.

Disrupted fear inhibition is a characteristic of many anxiety disorders. Investigations into the neural mechanisms responsible for inhibiting fear will improve understanding of the essential circuits involved, and facilitate development of treatments that promote their activity. Within the basolateral amygdala (BLA), Thy1-expressing neuron activity has been characterized by us and others as promoting fear inhibition to discrete fear cues by influencing consolidation of cued fear learning or cued fear extinction. Here, we evaluated how activating BLA Thy1-expressing neurons using DREADDs affected the consolidation, expression, reconsolidation, and extinction of contextual fear. Using an inhibitory avoidance paradigm, our present findings indicate a similar involvement of BLA Thy1-expressing neuron activity in the consolidation and extinction, but not expression, of fear. Importantly, our data also provide the first evidence for involvement of these neurons in inhibiting fear reconsolidation. Therefore, these data enhance our understanding of the roles that Thy1-expressing neurons within the BLA play in inhibiting fear when examining avoidance, in addition to the already established role in Pavlovian fear paradigms. Future investigations should further explore the circuits responsible for these contextual effects modulated by BLA Thy1 neuron activation, and could promulgate development of therapies targeting these neurons and their downstream effectors.

Constitutive plasma membrane monoamine transporter (PMAT, Slc29a4) deficiency subtly affects anxiety-like and coping behaviours.

Originally, uptake-mediated termination of monoamine (e.g., serotonin and dopamine) signalling was believed to only occur via high-affinity, low-capacity transporters ("uptake1 ") such as the serotonin or dopamine transporters, respectively. Now, the important contribution of a second low-affinity, high-capacity class of biogenic amine transporters has been recognised, particularly in circumstances when uptake1 transporter function is reduced (e.g., antidepressant treatment). Pharmacologic or genetic reductions in uptake1 function can change locomotor, anxiety-like or stress-coping behaviours. Comparable behavioural investigations into reduced low-affinity, high-capacity transporter function are lacking, in part, due to a current dearth of drugs that selectively target particular low-affinity, high-capacity transporters, such as the plasma membrane monoamine transporter. Therefore, the most direct approach involves constitutive genetic knockout of these transporters. Other groups have reported that knockout of the low-affinity, high-capacity organic cation transporters 2 or 3 alters anxiety-like and stress-coping behaviours, but none have assessed behaviours in plasma membrane monoamine transporter knockout mice. Here, we evaluated adult male and female plasma membrane monoamine transporter wild-type, heterozygous and knockout mice in locomotor, anxiety-like and stress-coping behavioural tests. A mild enhancement of anxiety-related behaviour was noted in heterozygous mice. Active-coping behaviour was modestly and selectively increased in female knockout mice. These subtle behavioural changes support a supplemental role of plasma membrane monoamine transporter in serotonin and dopamine uptake, and suggest sex differences in transporter function should be examined more closely in future investigations.

A film set for the elicitation of emotion in research: A comprehensive catalog derived from four decades of investigation.

Emotions are highly influential to many psychological processes. Indeed, research employing emotional stimuli is rapidly escalating across the field of psychology. However, challenges remain regarding discrete evocation of frequently co-elicited emotions such as amusement and happiness, or anger and disgust. Further, as much contemporary work in emotion employs college students, we sought to additionally evaluate the efficacy of film clips to discretely elicit these more challenging emotions in a young adult population using an online medium. The internet is an important tool for investigating responses to emotional stimuli, but validations of emotionally evocative film clips across laboratory and web-based settings are limited in the literature. An additional obstacle is identifying stimuli amidst the numerous film clip validation studies. During our investigation, we recognized the lack of a categorical database to facilitate rapid identification of useful film clips for individual researchers' unique investigations. Consequently, here we also sought to produce the first compilation of such stimuli into an accessible and comprehensive catalog. We based our catalog upon prior work as well as our own, and identified 24 articles and 295 film clips from four decades of research. We present information on the validation of these clips in addition to our own research validating six clips using online administration settings. The results of our search in the literature and our own study are presented in tables designed to facilitate and improve a selection of highly valid film stimuli for future research.

Perspectives on fear generalization and its implications for emotional disorders.

Although generalization to conditioned stimuli is not a new phenomenon, renewed interest in understanding its biological underpinning has stemmed from its association with a number of anxiety disorders. Generalization as it relates to fear processing is a temporally dynamic process in which animals, including humans, display fear in response to similar yet distinct cues or contexts as the time between training and testing increases. This Review surveys the literature on contextual fear generalization and its relation to several views of memory, including systems consolidation, forgetting, and transformation hypothesis, which differentially implicate roles of the hippocampus and neocortex in memory consolidation and retrieval. We discuss recent evidence on the neurobiological mechanisms contributing to the increase in fear generalization over time and how generalized responding may be modulated by acquisition, consolidation, and retrieval mechanisms. Whereas clinical perspectives of generalization emphasize a lack of fear inhibition to CS- cues or fear toward intermediate CS cues, the time-dependent nature of generalization and its relation to traditional views on memory consolidation and retrieval are often overlooked. Understanding the time-dependent increase in fear generalization has important implications not only for understanding how generalization contributes to anxiety disorders but also for understanding basic long-term memory function. © 2016 Wiley Periodicals, Inc.

Hippocampal GABAB(1a) Receptors Constrain Generalized Contextual Fear.

Many anxiety disorders are characterized by generalization of fear responses to neutral or ambiguous stimuli. Therefore, a comprehensive understanding of the mechanisms contributing to generalized fear is essential for formulating successful treatments for anxiety disorders. Previous research shows that GABA-mediated presynaptic inhibition has a critical role in cued fear generalization, as animals with genetically deleted presynaptic GABAB(1a) receptors cannot discriminate between CS+ and CS- tones. Work from our laboratory has further identified that GABAB(1a) receptors are necessary for maintaining contextual memory precision, thereby constraining generalized contextual fear. We previously found that GABAB(1a) KO mice show generalized fear to a neutral context 24 h after training, but not 2 h after training. A similar pattern was observed with object location and recognition, suggesting that this receptor subtype affects consolidation and/or retrieval of precise contextual and spatial memories. Here we sought to specifically examine the involvement of GABAB(1a) receptors in consolidation or retrieval of a precise fear memory. To do so, we infused a selective GABAB(1a) receptor antagonist, CGP 36216, intracerebroventricularly (ICV), or locally into the dorsal hippocampus, ventral hippocampus, or anterior cingulate cortex (ACC), during consolidation and retrieval of context fear training. Blockade of GABAB(1a) receptors through ICV, dorsal hippocampal, or ventral hippocampal infusions 'after' training (consolidation) resulted in fear generalization to the neutral context when mice were tested 24, but not 6 h after training. Post-training infusions of CGP into the ACC, however, did not promote generalized fear. In addition, ICV, dorsal hippocampal, ventral hippocampal, or ACC infusions immediately 'before' testing (retrieval) did not result in context fear generalization. These data suggest that GABA-mediated presynaptic inhibition is not critical for retrieval of precise contextual memory, but rather has an important role in the long-term consolidation of precise contextual memories and constrains generalized fear responses.

A Novel Interaction between Tryptophan Hydroxylase 2 (TPH2) Gene Polymorphism (rs4570625) and BDNF Val66Met Predicts a High-Risk Emotional Phenotype in Healthy Subjects.

Poor inhibitory processing of negative emotional content is central to many psychiatric disorders, including depression and anxiety. Moreover, increasing evidence suggests that core aspects of emotion-inhibitory processing are largely inherited and as such may represent a key intermediate or risk-related phenotype for common affective diseases (e.g., unipolar depressive, anxiety disorders). The current study employed a candidate-gene approach in order to most effectively examine this complex behavioral phenotype. We examined the novel interaction between BDNF (Val66Met) and TPH2 (rs4570625) polymorphisms and their influence on behavioral inhibition of negative emotion in two independent investigations of healthy adults. BDNF Met carriers consistently report greater symptoms of affective disease and display corresponding behavioral rigidity, while TPH2 T carriers display poor inhibitory processing. These genotypes are traditionally perceived as 'risk' genotypes when compared to their respective major Val and G homozygous genotypes, but evidence is mixed. Recent studies in humans and mutant mouse models suggest biological epistasis between BDNF and genes involved in serotonin regulation. Moreover, polymorphisms in the TPH2 gene may have greater influence on serotonergic function than other more commonly studied polymorphisms (e.g., 5-HTTLPR). We observed consistent evidence across two different emotion-inhibition paradigms, one with high internal validity (Study 1, n = 119) and one with high ecological validity (Study 2, n = 115) that the combination of Val/Val and G/G genotypes was clearly associated with impaired inhibition of negative emotional content. This was followed by individuals carrying the BDNF-Met allele (including Met/Val and Met/Met) when combined with the TPH2-T allele (including T/G and T/T combinations). The consistency of these results across tasks and studies suggests that these two groups may be particularly vulnerable to the most common psychiatric disorders and should be targets for future clinical investigation.

Corticosterone may interact with peripubertal development to shape adult resistance to social defeat.

Studies of social stress in adult mice have revealed two distinct defeat-responsive behavioral phenotypes; "susceptible" and "resistant," characterized by social avoidance and social interaction, respectively. Typically, these phenotypes are observed at least 1day after the last defeat in adults, but may extend up to 30days later. The current study examined the impact of peripubertal social defeat on immediate (1day) and adult (30day) social stress phenotypes and neuroendocrine function in male C57BL/6 mice. Initially, peripubertal (P32) mice were resistant to social defeat. When the same mice were tested for social interaction again as adults (P62), two phenotypes emerged; a group of mice were characterized as susceptible evidenced by significantly lower social interaction, whereas the remaining mice exhibited normal social interaction, characteristic of resistance. A repeated analysis of corticosterone revealed that the adult (P62) resistant mice had elevated corticosterone following the social interaction test as juveniles. This was when all mice, regardless of adult phenotype, displayed equivalent levels of social interaction. Peripubertal corticosterone was positively correlated with adult social interaction levels in defeated mice, suggesting early life stress responsiveness impacts adult social behavior. In addition, adult corticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN) was elevated in all defeated mice, but there were no differences in CRF mRNA expression between the phenotypes. Thus, there is a delayed appearance of social stress-responsive phenotypes suggesting that early life stress exposure, combined with the resultant physiological responses, may interact with pubertal development to influence adult social behavior.