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Context Traumatic experiences in early childhood are associated with increased risk for developing stress-related disorders, which are linked to structural brain abnormalities. However, it is unclear if these volumetric brain changes are present before disease onset or reflect the consequences of the disease progression. Objective To identify structural abnormalities in the nonhuman primate brain that may predict increased risk for stress-related neuropsychiatric disorders in humans. Design Rhesus monkeys were divided in two groups at birth: a group raised with their mothers and other juvenile and adult animals (mother-reared, MR), and a group raised with three age-matched monkeys only (peer-reared, PR). Anatomical brain images were acquired in juvenile male and female rhesus monkeys using magnetic resonance imaging. Main Outcome Measures Volumetric measures of the anterior cingulate cortex, medial prefrontal cortex, hippocampus, corpus callosum and cerebellar vermis were compared between MR (n=15) and PR animals (n=13). Results Compared to MR monkeys, we found an enlarged vermis, dorsomedial prefrontal and dorsal anterior cingulate cortex in PR monkeys but no differences in the corpus callosum and hippocampus. Conclusions Peer-rearing during infancy induces enlargements in stress-sensitive brain regions. These changes may be a structural phenotype for an increased risk to stress-related neuropsychiatric disorders in humans.

In the rat, both the medial and lateral prefrontal cortices (PFC; mPFC and 1PFC, respectively) have direct connections with limbic structures that are important in the expression of fear and anxiety. The present study investigated the behavioral effects of excitotoxic lesions of either the mPFC or the 1PFC on conditioned and unconditioned fear paradigms. In both unconditioned fear paradigms (open field, elevated plus-maze), lesions of the mPFC decreased anxiety. In fear conditioning, 1PFC lesions substantially increased freezing throughout the different phases of the experiment, whereas mPFC lesions increased freezing to contextual cues and showed reduced freezing to discrete cues. These results support the functional role of the PFC in mediating or modulating central states of fear and anxiety and suggest a functional dissociation between the 1PFC and mPFC in their role in fear and anxiety.In many animal species, the stress response is expressed both behaviorally, by fear and anxiety states characterized by cessation of ongoing behavior and increased reactivity to environmental stimuli, and physiologically, by alterations in cardiovascular function, changes in autonomic tone, and activation of the neuroendocrine axes. Several lines of evidence indicate that the prefrontal cortex (PFC) is involved in the control of stress and emotional behavior. The prefrontal cortex is defined as the cortex of the anterior pole of the mammalian brain, which predominantly receives projections from the mediodorsal thalamic nucleus. In the rat, the PFC has been divided into two distinct regions, a medial and a lateral PFC (mPFC and 1PFC, respectively), on the basis of functional and hodological criteria.Anatomical studies have shown that both the mPFC and the 1PFC have direct connections with limbic structures, such as the amygdala, the hypothalamus, the nucleus accumbens, and the hippocampus (Ferine

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Valid animal models of psychopathology need to include behavioural readouts informed by human findings. In the probabilistic reversal learning (PRL) task, human subjects are confronted with serial reversal of the contingency between two operant stimuli and reward/punishment and, superimposed on this, a low probability (0.2) of punished correct responses/rewarded incorrect responses. In depression, reward-stay and reversals completed are unaffected but response-shift following punished correct response trials, referred to as negative feedback sensitivity (NFS), is increased. The aims of this study were to: establish an operant spatial PRL test appropriate for mice; obtain evidence for the processes mediating reward-stay and punishment-shift responding; and assess effects thereon of genetically- and pharmacologically-altered serotonin (5-HT) function. The study was conducted with wildtype (WT) and heterozygous mutant (HET) mice from a 5-HT transporter (5-HTT) null mutant strain. Mice were mildly food deprived and reward was sugar pellet and punishment was 5-s time out. Mice exhibited high motivation and adaptive reversal performance. Increased probability of punished correct response (PCR) trials per session (p = 0.1, 0.2 or 0.3) led to monotonic decrease in reward-stay and reversals completed, suggesting accurate reward prediction. NFS differed from chance-level at p PCR = 0.1, suggesting accurate punishment prediction, whereas NFS was at chance-level at p = 0.2-0.3. At p PCR = 0.1, HET mice exhibited lower NFS than WT mice. The 5-HTT blocker escitalopram was studied acutely at p PCR = 0.2: a low dose (0.5-1.5 mg/kg) resulted in decreased NFS, increased reward-stay and increased reversals completed, and similarly in WT and HET mice. This study demonstrates that testing PRL in mice can provide evidence on the regulation of reward and punishment processing that is, albeit within certain limits, of relevance to human emotional-cognitive processing, its dysfunction and treatment.

Human studies have suggested an association between a variable length polymorphism in the serotonin transporter gene promoter region and vulnerability to anxiety and depression. Relative to the long (l) allele, the short (s) allele increases the risk of developing depression in individuals exposed to stressful life events. An orthologue of the human variant is present in rhesus macaques and allows for studies in animals exposed to stress. Here, we used an established model of early life stress exposure, in which rhesus macaques are raised without adults in a group of peers (peer-only reared [PR]), or with their mothers. At 6 months of age, animals were subjected to 4-day long social separations for 4 consecutive weeks, with 3 days of reunion in between. Data were collected during both the acute (Day 1) and chronic phases (Days 2-4) of separation. Behavioral factors were separately extracted for each phase of separation. For acute separation, the behavioral factors generated were despair and behavioral pathology and, for the chronic phase despair, agitation, and behavioral pathology. During both phases of social separation, PR l/s animals were more likely to exhibit pathological behaviors, whereas PR l/l monkeys show higher levels of despair compared to the other three groups. These findings indicate that early stress affects the behavioral response to separation differently as a function of recombinant human serotonin transporter linked polymorphic repeat genotype and suggest that carriers of the s allele are not only more anxious but may also be more vulnerable to developing behavioral pathology in the face of chronic adversity.

Background-Traumatic experiences in early childhood are associated with increased risk for developing mood and anxiety disorders later in life. Low serotonin 1A receptor (5-HT 1A R) density during development has been proposed as a trait-like characteristic leading to increased vulnerability of stress-related neuropsychiatric disorders.