MAOA methylation is associated with impulsive and antisocial behaviour: dependence on allelic variation, family environment and diet.

Congenital absence of monoamine oxidase A (MAO-A) activity predisposes to antisocial impulsive behaviour, and the MAOA uVNTR low-expressing genotype (MAOA-L) together with childhood maltreatment is associated with similar phenotypes in males. A possible explanation of how family environment may lead to such behaviour involves DNA methylation. We have assessed MAOA methylation and impulsive/antisocial behaviour in 121 males from the Estonian Children Personality Behaviour and Health Study. Of the 12 CpG sites measured, methylation levels at the locus designated CpG3 were significantly lower in subjects with antisocial behaviour involving police contact. CpG3 methylation was lower in subjects with alcohol use disorder by age 25, but only in MAOA-H genotype. No correlation between MAOA CpG3 methylation levels and adaptive impulsivity was found at age 15, but in MAOA-L genotype a positive correlation appeared by age 18. By age 25, this positive correlation was no longer observed in subjects with better family relationships but had increased further with experience of adversity within the family. MAOA CpG3 methylation had different developmental dynamics in relation to maladaptive impulsivity. At age 18, a positive correlation was observed in MAOA-L genotype with inferior family relationships and a negative correlation was found in MAOA-H with superior home environment; both of these associations had disappeared by age 25. CpG3 methylation was associated with dietary intake of several micronutrients, most notable was a negative correlation with the intake of zinc, but also with calcium, potassium and vitamin E; a positive correlation was found with intake of phosphorus. In conclusion, MAOA CpG3 methylation is related to both maladaptive and adaptive impulsivity in adolescence in MAOA-L males from adverse home environment. By young adulthood, this relationship with maladaptive impulsivity had disappeared but with adaptive impulsivity strengthened. Thus, MAOA CpG3 methylation may serve as a marker for adaptive developmental neuroplasticity in MAOA-L genotype. The mechanisms involved may include dietary factors.

Association of Impulsivity With Food, Nutrients, and Fitness in a Longitudinal Birth Cohort Study.

BACKGROUND: Impulsivity is a psychiatric vulnerability factor strongly associated with substance abuse but also with unhealthy diet. Whether these associations extend to specific nutrients is largely unknown. Therefore, we investigated the longitudinal association between diet, cardiorespiratory fitness, and 2 impulsivity dimensions in a representative sample of south Estonian adolescents and young adults. Impulsivity and dietary intake were measured 3 times in 2 birth cohorts at regular intervals in individuals aged 15 to 33 years. METHODS: The sample included 2 birth cohorts of the longitudinal Estonian Children Personality Behaviour and Health Study. The analytic sample size consisted of 2883 observations (56.4% females). The primary outcomes were adaptive and maladaptive impulsivity scores measured by an original 24-item Likert-type questionnaire. Impulsivity scores were predicted from the food diaries data converted into nutrient categories. A linear mixed-effects approach was used to model the time dependence between observations. RESULTS: Lower maladaptive impulsivity was associated with higher cardiorespiratory fitness (ß = -.07; 95% CI = -0.12; -0.03). Higher maladaptive impulsivity was associated with lower dietary intake of zinc (ß = -.10; -0.15; -0.06) and vegetables (ß = -.04; -0.07; -0.01) and higher intake of sodium (ß = .06; 0.02; 0.10). Vitamin B6 was positively associated with adaptive impulsivity (ß = .04; 0.01; 0.07). Additionally, some of the adjusted models showed significant but weak associations with selenium, alcohol, fish, and cereal products. CONCLUSIONS: Food choice may affect the neurochemistry and therefore regulate the manifestations of impulsivity. We identified associations between several (micro)nutrients and maladaptive impulsivity.

Cholecystokinin B receptor gene polymorphism (rs2941026) is associated with anxious personality and suicidal thoughts in a longitudinal study.

OBJECTIVES: Cholecystokinin is a neuropeptide with a role in the neurobiology of adaptive behaviour that is implicated in anxiety disorders, while the underlying mechanisms currently remain insufficiently explained. The rs2941026 variation in the cholecystokinin B receptor gene has previously been associated with trait anxiety. Our aim was to investigate associations between the CCKB receptor gene polymorphism rs2941026 with anxiety, personality, depressiveness and suicidality in a longitudinal study of late adolescence and early adulthood. METHODS: We used reports on trait and state anxiety, depressiveness and suicidal thoughts, as well as Affective Neuroscience Personality Scales, from the two birth cohorts of the Estonian Children Personality, Behaviour and Health Study. We measured associations between the CCKBR gene rs2941026 and anxiety-related phenotypes both longitudinally and cross-sectionally at ages 15, 18, 25 and 33. RESULTS: Homozygosity for both alleles of the CCKBR rs2941026 was associated with higher trait and state anxiety in the longitudinal analysis. Cross-sectional comparisons were statistically significant at ages 18 and 25 for trait anxiety and at ages 25 and 33 for state anxiety. Higher depressiveness and suicidal thoughts were associated with the A/A genotype at age 18. Additionally, homozygosity for the A-allele was related to higher FEAR and SADNESS in the Affective Neuroscience Personality Scales. The genotype effects were more apparent in females, who displayed higher levels of negative affect overall. CONCLUSIONS: CCKBR genotype is persistently associated with negative affect in adolescence and young adulthood. The association of the CCKBR rs2941026 genotype with anxiety-related phenotypes is more pronounced in females.

Properties of visually guided saccadic behavior and bottom-up attention in marmoset, macaque, and human.

Saccades are stereotypic behaviors whose investigation improves our understanding of how primate brains implement precise motor control. Furthermore, saccades offer an important window into the cognitive and attentional state of the brain. Historically, saccade studies have largely relied on macaques. However, the cortical network giving rise to the saccadic command is difficult to study in macaques because relevant cortical areas lie in deep sulci and are difficult to access. Recently, a New World monkey. the marmoset, has garnered attention as an alternative to macaques because of advantages including its smooth cortical surface. However, adoption of the marmoset for oculomotor research has been limited due to a lack of in-depth descriptions of marmoset saccade kinematics and their ability to perform psychophysical tasks. Here, we directly compare free-viewing and visually guided behavior of marmoset, macaque, and human engaged in identical tasks under similar conditions. In the video free-viewing task, all species exhibited qualitatively similar saccade kinematics up to 25° in amplitude although with different parameters. Furthermore, the conventional bottom-up saliency model predicted gaze targets at similar rates for all species. We further verified their visually guided behavior by training them with step and gap saccade tasks. In the step paradigm, marmosets did not show shorter saccade reaction time for upward saccades whereas macaques and humans did. In the gap paradigm, all species showed similar gap effect and express saccades. Our results suggest that the marmoset can serve as a model for oculomotor, attentional, and cognitive research while we need to be aware of their difference from macaque or human.NEW & NOTEWORTHY We directly compared the results of a video free-viewing task and visually guided saccade tasks (step and gap) among three different species: marmoset, macaque, and human. We found that all species exhibit qualitatively similar saccadic kinematics and saliency-driven saccadic behavior albeit with different parameters. Our results suggest that the marmoset possesses similar neural mechanisms to macaque and human for saccadic control, and it is an appropriate model to study neural mechanisms for active vision and attention.

Cortical projections to the superior colliculus in grey squirrels (Sciurus carolinensis).

The superior colliculus is an important midbrain structure involved with integrating information from varying sensory modalities and sending motor signals to produce orienting movements towards environmental stimuli. Because of this role, the superior colliculus receives a multitude of sensory inputs from a wide variety of subcortical and cortical structures. Proportionately, the superior colliculus of grey squirrels is among the largest in size of all studied mammals, suggesting the importance of this structure in the behavioural characteristics of grey squirrels. Yet, our understanding of the connections of the superior colliculus in grey squirrels is lacking, especially with respect to possible cortical influences. In this study, we placed anatomical tracer injections within the medial aspect of the superior colliculus of five grey squirrels (Sciurus carolinensis) and analysed the areal distribution of corticotectal projecting cells in flattened cortex. V1 projections to the superior colliculus were studied in two additional animals. Our results indicate that the superior colliculus receives cortical projections from visual, higher order somatosensory, and higher order auditory regions, as well as limbic, retrosplenial and anterior cingulate cortex. Few, if any, corticotectal projections originate from primary motor, primary somatosensory or parietal cortical regions. This distribution of inputs is similar to the distribution of inputs described in other rodents such as rats and mice, yet the lack of inputs from primary somatosensory and motor cortex is features of corticotectal inputs more similar to those observed in tree shrews and primates, possibly reflecting a behavioural shift from somatosensory (vibrissae) to visual navigation.

Subcortical barrelette-like and barreloid-like structures in the prosimian galago (Otolemur garnetti).

Galagos are prosimian primates that resemble ancestral primates more than most other extant primates. As in many other mammals, the facial vibrissae of galagos are distributed across the upper and lower jaws and above the eye. In rats and mice, the mystacial macrovibrissae are represented throughout the ascending trigeminal pathways as arrays of cytoarchitecturally distinct modules, with each module having a nearly one-to-one relationship with a specific facial whisker. The macrovibrissal representations are termed barrelettes in the trigeminal somatosensory brainstem, barreloids in the ventroposterior medial subnucleus of the thalamus, and barrels in primary somatosensory cortex. Despite the presence of facial whiskers in all nonhuman primates, barrel-like structures have not been reported in primates. By staining for cytochrome oxidase, Nissl, and vesicular glutamate transporter proteins, we show a distinct array of barrelette-like and barreloid-like modules in the principal sensory nucleus, the spinal trigeminal nucleus, and the ventroposterior medial subnucleus of the galago, Otolemur garnetti. Labeled terminals of primary sensory neurons in the brainstem and cell bodies of thalamocortically projecting neurons demonstrate that barrelette-like and barreloid-like modules are located in areas of these somatosensory nuclei that are topographically consistent with their role in facial touch. Serendipitously, the plane of section that best displays the barreloid-like modules reveals a remarkably distinct homunculus-like patterning which, we believe, is one of the clearest somatotopic maps of an entire body surface yet found.

Middle-range exploratory activity in adult rats suggests higher resilience to chronic social defeat.

OBJECTIVE: Stressful life events play an important role in the aetiology of human mood disorders and are frequently modelled by chronic social defeat (SD) in rodents. Exploratory phenotype in rats is a stable trait that is likely related to inter-individual differences in reactivity to stress. The aim of the study was to confirm that low levels of exploratory activity (LE) are, in rodents, a risk factor for passive stress coping, and to clarify the role of medium (ME) and high (HE) exploratory disposition in the sensitivity to SD. METHODS: We examined the effect of SD on male Wistar rats with LE, ME, and HE activity levels as measured in the exploration box. After SD, the rats were evaluated in social preference, elevated zero maze, and open-field tests. Brain tissue levels of monoamines were measured by high-performance liquid chromatography. RESULTS: Rats submitted to SD exhibited lower weight gain, higher sucrose consumption, showed larger stress-induced hyperthermia, lower levels of homovanillic acid in the frontal cortex, and higher levels of noradrenaline in the amygdala and hippocampus. Open-field, elevated zero maze, and social preference tests revealed the interaction between stress and phenotype, as only LE-rats were further inhibited by SD. ME-rats exhibited the least reactivity to stress in terms of changes in body weight, stress-induced hyperthermia, and sucrose intake. CONCLUSION: Both low and high novelty-related activity, especially the former, are associated with elevated sensitivity to social stress. This study shows that both tails of a behavioural dimension can produce stress-related vulnerability.

Cingulate cortex shapes early postnatal development of social vocalizations.

The social dynamics of vocal behavior has major implications for social development in humans. We asked whether early life damage to the anterior cingulate cortex (ACC), which is closely associated with socioemotional regulation more broadly, impacts the normal development of vocal expression. The common marmoset provides a unique opportunity to study the developmental trajectory of vocal behavior, and to track the consequences of early brain damage on aspects of social vocalizations. We created ACC lesions in neonatal marmosets and compared their pattern of vocalization to that of age-matched controls throughout the first 6 weeks of life. We found that while early life ACC lesions had little influence on the production of vocal calls, developmental changes to the quality of social contact calls and their associated syntactical and acoustic characteristics were compromised. These animals made fewer social contact calls, and when they did, they were short, loud and monotonic. We further determined that damage to ACC in infancy results in a permanent alteration in downstream brain areas known to be involved in social vocalizations, such as the amygdala and periaqueductal gray. Namely, in the adult, these structures exhibited diminished GABA-immunoreactivity relative to control animals, likely reflecting disruption of the normal inhibitory balance following ACC deafferentation. Together, these data indicate that the normal development of social vocal behavior depends on the ACC and its interaction with other areas in the vocal network during early life.

Diffusion MRI anisotropy in the cerebral cortex is determined by unmyelinated tissue features.

Diffusion magnetic resonance imaging (dMRI) is commonly used to assess the tissue and cellular substructure of the human brain. In the white matter, myelinated axons are the principal neural elements that shape dMRI through the restriction of water diffusion; however, in the gray matter the relative contributions of myelinated axons and other tissue features to dMRI are poorly understood. Here we investigate the determinants of diffusion in the cerebral cortex. Specifically, we ask whether myelinated axons significantly shape dMRI fractional anisotropy (dMRI-FA), a measure commonly used to characterize tissue properties in humans. We compared ultra-high resolution ex vivo dMRI data from the brain of a marmoset monkey with both myelin- and Nissl-stained histological sections obtained from the same brain after scanning. We found that the dMRI-FA did not match the spatial distribution of myelin in the gray matter. Instead dMRI-FA was more closely related to the anisotropy of stained tissue features, most prominently those revealed by Nissl staining and to a lesser extent those revealed by myelin staining. Our results suggest that unmyelinated neurites such as large caliber apical dendrites are the primary features shaping dMRI measures in the cerebral cortex.

Activating effects of chronic variable stress in rats with different exploratory activity: association with dopamine d(1) receptor function in nucleus accumbens.

BACKGROUND/AIMS: Rats display persistent behavioural phenotypes of low (LE) versus high (HE) exploratory activity in the exploration box paradigm. LE rats that prefer passive coping strategies show differential dopaminergic activity in the striatum. The main hypothesis of this study was that chronic variable stress (CVS) would have a higher impact on LE rats. METHODS: Animals were submitted to a CVS regimen lasting 32 days that was followed by a behavioural test battery. The functional states of their dopamine D(1) and D(2) receptors were measured in the striatum and nucleus accumbens (NAcc). Cerebral oxidative metabolism was assessed via cytochrome c oxidase histochemistry in 65 brain regions. RESULTS: CVS decreased weight gain, to a higher extent in LE rats, and lowered the sucrose preference after the first week, but habituation to the anhedonic effect had developed by the end of the experiment. CVS did not change the behavioural phenotypes initially assigned. No effect of stress on D(2) receptor function was found. Chronically stressed animals exhibited higher levels of social interaction and D(1) receptor-mediated cAMP accumulation in the NAcc, but not in the striatum. CVS was associated with higher oxidative metabolism levels in the anteroventral thalamus, median raphe nuclei and central periaqueductal grey matter. These changes after stress did not depend upon the exploratory phenotype. CONCLUSION: This study revealed changes in brain biochemistry after habituation to CVS that might be implicated in successful adaptation to chronic stress.

Effect of Neuropeptide S Administration on Ultrasonic Vocalizations and Behaviour in Rats with Low vs. High Exploratory Activity.

Neuropeptide S (NPS) is a peptide neurotransmitter that in animal studies promotes wakefulness and arousal with simultaneous anxiety reduction, in some inconsistency with results in humans. We examined the effect of NPS on rat ultrasonic vocalizations (USV) as an index of affective state and on behaviour in novel environments in rats with persistent inter-individual differences in exploratory activity. Adult male Wistar rats were categorised as of high (HE) or low (LE) exploratory activity and NPS was administered intracerebroventricularly (i.c.v.) at a dose of 1.0 nmol/5 µL, after which USVs were recorded in the home-cage and a novel standard housing cage, and behaviour evaluated in exploration/anxiety tests. NPS induced a massive production of long and short 22 kHz USVs in the home cage that continued later in the novel environment; no effect on 50 kHz USVs were found. In LE-rats, the long 22 kHz calls were emitted at lower frequencies and were louder. The effects of NPS on behaviour appeared novelty- and test-dependent. NPS had an anxiolytic-like effect in LE-rats only in the elevated zero-maze, whereas in HE-rats, locomotor activity in the zero-maze and in a novel standard cage was increased. Thus NPS appears as a psychostimulant peptide but with a complex effect on dimensions of affect.

Comprehensive mapping of cytochrome c oxidase activity in the rat brain after sub-chronic ketamine administration.

Ketamine is a noncompetitive antagonist of glutamatergic N-methyl-d-aspartate receptors. Its acute effects on healthy volunteers and schizophrenia patients mimic some acute psychotic, but also cognitive and negative symptoms of schizophrenia, and subchronic treatment with ketamine has been used as an animal model of psychotic disorders. Glutamatergic neurotransmission is tightly coupled to oxidative metabolism in the brain. Quantitative histochemical mapping of cytochrome c oxidase (COX) activity, which reflect long-term energy metabolism, was carried out in rats that received a daily subanaesthetic dose (30 mg/kg) of ketamine for 10 days. In total, COX activity was measured in 190 brain regions to map out metabolic adaptations to the subchronic administration of ketamine. Ketamine treatment was associated with elevated COX activity in nine brain sub-regions in sensory thalamus, basal ganglia, cortical areas, hippocampus and superior colliculi. Changes in pairwise correlations between brain regions were studied with differential correlation analysis. Ketamine treatment was associated with the reduction of positive association between brain regions in 66 % of the significant comparisons. Different layers of the superior colliculi showed the strongest effects. Changes in other visual and auditory brain centres were also of note. The locus coeruleus showed opposite pattern of increased coupling to mainly limbic brain regions in ketamine-treated rats. Our study replicated commonly observed activating effects of ketamine in the hippocampus, cingulate cortex, and basal ganglia. The current study is the first to extensively map the oxidative metabolism in the CNS in the ketamine model of schizophrenia. It shows that ketamine treatment leads to the re-organization of activity in sensory and memory-related brain circuits.

Cerebral oxidative metabolism mapping in four genetic mouse models of anxiety and mood disorders.

The psychopathology of depression is highly complex and the outcome of studies on animal models is divergent. In order to find brain regions that could be metabolically distinctively active across a variety of mouse depression models and to compare the interconnectivity of brain regions of wild-type and such genetically modified mice, histochemical mapping of oxidative metabolism was performed by the measurement of cytochrome oxidase activity. We included mice with the heterozygous knockout of the vesicular glutamate transporter (VGLUT1-/+), full knockout of the cannabinoid 1 receptor (CB1-/-), an anti-sense knockdown of the glucocorticoid receptor (GRi) and overexpression of the human 5-hydroxytryptamine transporter (h5-HTT). Altogether 76 mouse brains were studied to measure oxidative metabolism in one hundred brain regions, and the obtained dataset was submitted to a variety of machine learning algorithms and multidimensional scaling. Overall, the top brain regions having the largest contribution to classification into depression model were the lateroanterior hypothalamic nucleus, the anterior part of the basomedial amygdaloid nucleus, claustrum, the suprachiasmatic nucleus, the ventromedial hypothalamic nucleus, and the anterior hypothalamic area. In terms of the patterns of inter-regional relationship between wild-type and genetically modified mice there was little overall difference, while the most deviating brain regions were cortical amygdala and ventrolateral and ventral posteromedial thalamic nuclei. The GRi mice that most clearly differed from their controls exhibited deviation of connectivity for a number of brain regions, such as ventrolateral thalamic nucleus, the intermediate part of the lateral septal nucleus, the anteriodorsal part of the medial amygdaloid nucleus, the medial division of the central amygdaloid nucleus, ventral pallidum, nucleus of the vertical limb of the diagonal band, anteroventral parts of the thalamic nucleus and parts of the bed nucleus of the stria terminalis. Conclusively, the GRi mouse model was characterized by changes in the functional connectivity of the extended amygdala and stress response circuits.

Changes in regional long-term oxidative metabolism induced by partial serotonergic denervation and chronic variable stress in rat brain.

Stressful experiences and genetic predisposition have both independent and interactive contributions to the development of depression. The serotonergic system is involved in the development of depression, and administration of neurotoxins that specifically compromise its function leads to symptoms of affective disorders. In order to find out which brain regions are most affected by stress, partial serotonergic denervation and their combination, chronic variable stress (CVS) was applied for 3 week. Serotonergic denervation was elicited by parachloroampetamine (PCA, 2mg/kg), and cytochrome oxidase histochemistry was used to characterize the long-term levels of neuronal oxidative energy metabolism. PCA pretreatment blocked the increase in oxidative activity in chronically stressed rats in medial preoptic area, cortical and medial amygdala. PCA raised oxidative activity compared to control animals in substantia nigra and ventrolateral division of laterodorsal thalamus. CVS reduced the oxidative activity induced by PCA in suprachiasmatic hypothalamus, anteroventral thalamus, hippocampal CA3 region and cortical amygdala. In the dorsal part of the anterior olfactory nucleus chronic stress blocked the decrease in oxidative activity evoked by PCA. Conclusively, partial serotonergic denervation with PCA and chronic variable stress both had independent effects on long-term energy metabolism in several rat brain structures, tending to increase it. However, partial serotonergic denervation by parachloroampetamine and chronic variable stress had in many brain regions an interactive effect on energy metabolism, each factor reducing the effect of the other, which could reflect the weakening of adaptive mechanisms.

Tickling-induced 50-kHz ultrasonic vocalization is individually stable and predicts behaviour in tests of anxiety and depression in rats.

Manipulation of juvenile rats in a way that mimics the rough-and-tumble play and resembles tickling elicits 50-kHz ultrasonic vocalizations (USVs) that have been proposed as a measure of positive affect. In the present experiments the stability of the 50-kHz USV response (chirping) over 1.5 months of daily manipulation and the effect of tickling was studied. By the second week of tickling rats of both sexes developed a level of 50-kHz USVs that remained individually characteristic. During tickling the rats also emitted low levels of 22-kHz USVs. No correlation was found between the two types of USVs. In tests used in anxiety and depression research, tickling on its own had an anxiolytic effect in many experimental settings. Significantly lower levels of [(35)S]GTPgammaS binding to the dopamine-activated receptor-G protein complex in striatum and serotonin transporter levels in the frontal cortex were found in female control rats as compared to males. These differences were eliminated by tickling. Rats which expressed high level of chirping (HC-rats) were similar to low-chirping (LC) rats in anxiety measures but had lower activity in an exploration test and lower sucrose preference. LC-rats adopted more active coping strategies in the forced swimming test. These findings suggest that there are individually characteristic 50-kHz USV response levels to tickling in rats, and that HC- and LC-rats are similar with regard to anxiety levels but have different coping strategies to novelty. The anxiolytic-like changes in behaviour that were brought about by tickling could be mediated by changes in dopamine- and serotonergic systems.

Cerebral oxidative metabolism in rats with high and low exploratory activity.

To reveal brain regions most significantly related to individual differences in exploratory behaviour, oxidative metabolism was measured by cytochrome c oxidase histochemistry in 2 months old Wistar rats with persistently high (HE) or low (LE) exploratory activity in a novel environment. LE-rats had significantly higher levels of oxidative metabolism in dorsal raphe and inferior colliculi. In contrast, HE-rats had higher metabolic activity in entorhinal cortex. In conclusion, rats with different exploratory styles differ in underlying cerebral activity as measured via oxidative metabolism in regions implicated in defensive behaviours and cognitive processing of sensory stimuli.

Revealing the cerebral regions and networks mediating vulnerability to depression: oxidative metabolism mapping of rat brain.

The large variety of available animal models has revealed much on the neurobiology of depression, but each model appears as specific to a significant extent, and distinction between stress response, pathogenesis of depression and underlying vulnerability is difficult to make. Evidence from epidemiological studies suggests that depression occurs in biologically predisposed subjects under impact of adverse life events. We applied the diathesis-stress concept to reveal brain regions and functional networks that mediate vulnerability to depression and response to chronic stress by collapsing data on cerebral long term neuronal activity as measured by cytochrome c oxidase histochemistry in distinct animal models. Rats were rendered vulnerable to depression either by partial serotonergic lesion or by maternal deprivation, or selected for a vulnerable phenotype (low positive affect, low novelty-related activity or high hedonic response). Environmental adversity was brought about by applying chronic variable stress or chronic social defeat. Several brain regions, most significantly median raphe, habenula, retrosplenial cortex and reticular thalamus, were universally implicated in long-term metabolic stress response, vulnerability to depression, or both. Vulnerability was associated with higher oxidative metabolism levels as compared to resilience to chronic stress. Chronic stress, in contrast, had three distinct patterns of effect on oxidative metabolism in vulnerable vs. resilient animals. In general, associations between regional activities in several brain circuits were strongest in vulnerable animals, and chronic stress disrupted this interrelatedness. These findings highlight networks that underlie resilience to stress, and the distinct response to stress that occurs in vulnerable subjects.

Mapping patterns of depression-related brain regions with cytochrome oxidase histochemistry: relevance of animal affective systems to human disorders, with a focus on resilience to adverse events.

The search for novel antidepressants may be facilitated by pre-clinical animal models that relay on specific neural circuit and related neurochemical endpoint measures, which are anchored in concrete neuro-anatomical and functional neural-network analyzes. One of the most important initial considerations must be which regions of the brain are candidates for the maladaptive response to depressogenic challenges. Consideration of persistent differences or changes in the activity of cerebral networks can be achieved by mapping oxidative metabolism in ethologically or pathogenetically relevant animal models. Cytochrome oxidase histochemistry is a technique suitable to detect regional long-term brain activity changes relative to control conditions and has been used in a variety of animal models. This work is summarized and indicates that major changes occur mainly in subcortical areas, highlighting specific brain regions where some alterations in regional oxidative metabolism may represent adaptive changes to depressogenic adverse life events, while others may reflect failures of adaptation. Many of these changes in oxidative metabolism may depend upon the integrity of serotonergic neurotransmission, and occur in several brain regions shown by other techniques to be involved in endogenous affective circuits that control emotional behaviors as well as related higher brain regions that integrate learning and cognitive information processing. These brain regions appear as primary targets for further identification of endophenotypes specific to affective disorders.

Brain responses to chronic social defeat stress: effects on regional oxidative metabolism as a function of a hedonic trait, and gene expression in susceptible and resilient rats.

Chronic social defeat stress, a depression model in rats, reduced struggling in the forced swimming test dependent on a hedonic trait-stressed rats with high sucrose intake struggled less. Social defeat reduced brain regional energy metabolism, and this effect was also more pronounced in rats with high sucrose intake. A number of changes in gene expression were identified after social defeat stress, most notably the down-regulation of Gsk3b and Map1b. The majority of differences were between stress-susceptible and resilient rats. Conclusively, correlates of inter-individual differences in stress resilience can be identified both at gene expression and oxidative metabolism levels.

Increased vulnerability to depressive-like behavior of mice with decreased expression of VGLUT1.

BACKGROUND: Many studies link depression to an increase in the excitatory-inhibitory ratio in the forebrain. Presynaptic alterations in a shared pathway of the glutamate/gamma-aminobutyric acid (GABA) cycle may account for this imbalance. Evidence suggests that decreased vesicular glutamate transporter 1 (VGLUT1) levels in the forebrain affect the glutamate/GABA cycle and induce helpless behavior. We studied decreased VGLUT1 as a potential factor enhancing a depressive-like phenotype in an animal model. METHODS: Glutamate and GABA synthesis as well as oxidative metabolism were studied in heterozygous mice for the VGLUT1+/- and wildtype. The regulation of neurotransmitter levels, proteins involved in the glutamate/GABA cycle, and behavior by both genotype and chronic mild stress (CMS) were studied. Finally, the effect of chronic imipramine on VGLUT1 control and CMS mice was studied. RESULTS: VGLUT1+/- mice showed increased neuronal synthesis of glutamate; decreased cortical and hippocampal GABA, VGLUT1, and excitatory amino acid transporter 1 (EAAT1) as well as helplessness and anhedonia. CMS induced an increase of glutamate and a decrease of GABA, the vesicular GABA transporter (VGAT), and glutamic acid decarboxylase 65 (GAD65) in both areas and led to upregulation of EAAT1 in the hippocampus. Moreover, CMS induced anhedonia, helplessness, anxiety, and impaired recognition memory. VGLUT1+/- CMS mice showed a combined phenotype (genotype plus stress) and specific alterations, such as an upregulation of VGLUT2 and hyperlocomotion. Moreover, an increased vulnerability to anhedonia and helplessness reversible by chronic imipramine was shown. CONCLUSIONS: These studies highlight a crucial role for decreased VGLUT1 in the forebrain as a biological mediator of increased vulnerability to chronic mild stress.