Differential impact of polysialyltransferase ST8SiaII and ST8iaIV knockout on social interaction and aggression

Previous studies using neuronal cell adhesion molecule (NCAM) -/- knockout (KO) mice provided evidence for a role of NCAMs in social behaviors. However, polysialic acid (PSA), the most important post-translational modification of NCAM, was also absent in these mice, which makes it difficult to distinguish between the specific involvement of either PSA or NCAM in social interactions. To address this issue, we assessed two lines of mice deficient for one of the two sialyltransferase enzymes required for the polysialylation of NCAM, sialyltransferase-X (St8SiaII or STX) and polysialyltransferase (ST8SiaIV or PST), in a series of tests for social behaviors. Results showed that PST KO mice display a decreased motivation in social interaction. This deficit can be partly explained by olfactory deficits and was associated with a clear decrease in PSA-NCAM expression in all brain regions analyzed (amygdala, septum, bed nucleus of the stria terminalis and frontal cortices). STX KO mice displayed both a decreased social motivation and an increased aggressive behavior that cannot be explained by olfactory deficits. This finding might be related to the reduced anxiety-like behavior, increased locomotion and stress-induced corticosterone secretion observed in these mice. Moreover, STX KO mice showed mild increase of PSA-NCAM expression in the lateral septum and the orbitofrontal cortex. Altogether, these findings support a role for PSA-NCAM in the regulation of social behaviors ranging from a lack of social motivation to aggression. They also underscore STX KO mice as an interesting animal model that combines a behavioral profile of violence and hyperactivity with reduced anxiety-like behavior.

Role of the HPA axis in the long-term programming of social behaviors by peripuberty stress

Vandana Veenit

Stress during childhood and adolescence enhances the risk of psychopathology later in life. In fact, exposure to stress during this period is known to predispose individuals to the development of psychopathologies such as depression and anxiety disorders later in life. Similarly, individuals subjected to fearful experiences or abuse during childhood and puberty exhibit violent behaviors in adulthood, as revealed in both human literature and animal studies. Previous work from our laboratory has shown that exposing peripuberty rats to fear experiences (such as synthetic fox odor and exposure to an elevated platform) following an unpredictable schedule, on a range of 7 specific days across P28 to P42 in male Wistar rats leads to reduced sociability, increased aggression, anxiety- and depression-like behaviors in adulthood. The hypothalamic pituitary adrenal (HPA) axis is one of the main physiological stress systems and various components of the HPA axis like corticotropin releasing hormone (CRH), glucocorticoids are modulated in response to early life experience. We therefore sought to investigate the role of HPA axis in long term programming of social and emotional behaviors as a result of peripuberty stress(PPS). We addressed this by manipulating (i) glucocorticoid system by two approaches, and, (ii) corticotropin releasing hormone (CRH) system. First, using male Wistar rats, we evaluated the consequences of administration of corticosterone following the same experimental schedule as for stress administration in our peripuberty stress paradigm (without actual stress exposure) on play behavior on postnatal day 44 (P44) and on behavioral tests of anxiety, aggression, sociability and depression in adulthood. Corticosterone response to novelty was also measured in adulthood. Our results show that, as compared to vehicle-, corticosterone-treated animals exhibit higher aggressive play behavior during adolescence, and escalated aggressive behavior in adulthood, while reduced sociability and decreased corticosterone response to novelty in adulthood. No differences were observed between groups on anxiety- and depression-like behavior tested later in life. Next, we examined whether pharmacological blockade of glucocorticoid receptor 30 minutes prior to peripuberty stress would prevent the consequences of peripuberty stress on emotional, social behavior and dysregulated gene expression. Our findings showed that administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty stress on behaviors related to the domain of aggression and sociability in adulthood without producing any effect on anxiety- and depression-like behavior tested later in life. Interestingly, administration of GR antagonist in PPS animals also reversed the effects of PPS on increased expression of GR and Trpc5 genes in central nucleus of amygdala. We also observed increased Crhr1 expression in limbic areas in peripuberty stressed animals which was not reversed by administration of GR antagonist in peripuberty stressed animals. Subsequently, we sought to evaluate the consequences of counteracting CRHR1 activation during early post-stress period on long-term behavioral consequences of peripuberty stress in tests for anxiety- and depression-like behaviors. Our results showed that administration of CRHR1 antagonist post peripuberty stress rescued the effects of peripuberty stress on depression-like behavior and to some extent on anxiety- like behavior. Taken together, our studies show that corticosterone administration during peripuberty largely mimics the behavioral alterations observed in peripuberty stressed animals in social realm, administration of glucocorticoid receptor antagonist on days of peripuberty stress prevents the effects of peripuberty on social domain and on increased expression of GR and Trpc5 genes in central nucleus of amygdala, and administration of CRHR1 antagonist post peripuberty stress rescued the effects of PPS on depression-like behavior and to some extent on anxiety-like behavior.

EPFL2013

Reto Bisaz, David Genoux, Maria del Carmen Sandi Perez

Most of the mechanisms involved in neural plasticity support cognition, and aging has a considerable effect on some of these processes. The neural cell adhesion molecule (NCAM) of the immunoglobulin superfamily plays a pivotal role in structural and functional plasticity and is required to modulate cognitive and emotional behaviors. However, whether aging is associated with NCAM alterations that might contribute to age-related cognitive decline is not currently known. In this study, we determined whether conditional NCAM-deficient mice display increased vulnerability to age-related cognitive and emotional alterations. We assessed the NCAM expression levels in the hippocampus and medial prefrontal cortex (mPFC) and characterized the performance of adult and aged conditional NCAM-deficient mice and their age-matched wild-type littermates in a delayed matching-to-place test in the Morris water maze and a delayed reinforced alternation test in the T-maze. Although aging in wild-type mice is associated with an isoform-specific reduction of NCAM expression levels in the hippocampus and mPFC, these mice exhibited only mild impairments in working/episodic-like memory performance. However, aged conditional NCAM-deficient mice displayed pronounced impairments in both the delayed matching-to-place and the delayed reinforced alternation tests. Importantly, the deficits of aged NCAM-deficient mice in these working/episodic-like memory tasks could not be attributed to increased anxiety-like behaviors or to differences in locomotor activity. Taken together, these data indicate that reduced NCAM expression in the forebrain might be a critical factor for the occurrence of cognitive impairments during aging.

Cold Spring Harbor Lab Press, Publications Dept2013

Implication of individual differences in glucocorticoid responsiveness to stress in the development of psychopathology-like behaviour and underlying neurobiology

Sophie Elizabeth Walker

The period around puberty is a critical window in development. It is a time of neuroendocrine and neuroanatomical lability, rendering individuals highly sensitive to stress. Indeed, early adversity increases risk for psychopathology. The mechanisms via which this vulnerability is differentially translated between individuals are not yet understood. Wistar rats exposed to psychogenic stressors around puberty show increased psychopathology-like behaviors at adulthood. Like humans, not all rats exposed to this stress develop in the same way, particularly with regard to aggression. The actions of glucocorticoids, the end product of hypothalamic-pituitary-adrenal (HPA) axis activations, mediate some alterations induced by peripuberty stress (PPS). Here we thus focused on assessing if individual differences in glucocorticoid responsiveness to stress influenced outcome following stress. We exposed male rats to PPS and later measured socio-affective behaviors and brain structure with magnetic resonance imaging. By applying a profiling approach we discerned two distinct neurodevelopmental trajectories arising from PPS. One led to the development of pathological aggression and reduced mean diffusivity in infralimbic cortex, amygdala and hippocampus. The other led to increased anxiety-like behavior and reduced sociability, with no evidence of alterations in brain structure. We assessed glucocorticoid responsiveness to PPS across the protocol and found that impaired habituation was associated with a more aggressive profile. Impaired habituation of glucocorticoid responses, shown by â35% of people, is heritable and associated with self-report of psychopathology-related indices. Considering this and our findings, we asked if constitutive differences in habituation to repeated stress were implicated in vulnerability to psychopathology. To answer this question, we developed a new animal model. We selectively bred lines of rats, enriching for stress habituation (âlow-lineâ) and lack of stress habituation (âhigh-lineâ). Once the lines were established, we assessed socio-affective behaviors and neuroendocrine phenotype of the rats. High-line rats displayed more aggression, anxiety-like, and depression-like behaviors. High-line rats had a distinct neuroendocrine phenotype, with enhanced corticosterone reactivity to acute stress, but no evidence for general HPA axis hyperactivity, and altered expression of several HPA axis related genes. Finally, we studied the interaction of the two risk factors in the development of behavioral alterations. Low- and high-line rats were exposed to PPS, and socio-affective behaviors and basal activation of the brain were later assessed. Both factors enhanced levels of anxiety-like and aggressive behavior, as well as increasing activity across the prefrontal cortex in a manner that was associated with increased behavioral inhibition. PPS had a differential impact on the lines, enhancing aggression in the stress-habituating low-line but not in the already high-aggressive, high-line rats. In summary, we established incidence of differential neurobehavioral trajectories following PPS, trajectories associated with differential glucocorticoid responsiveness across the stress. Constitutively impaired stress habituation increased psychopathology-like behavior in its own right, and this was not enhanced by exposure to PPS. In contrast, constitutively strong habituation enhanced sensitivity to the programming effects of PPS.

EPFL2016

Role of the HPA axis in the long-term programming of social behaviors by peripuberty stress

Vandana Veenit

EPFL2013

Implication of individual differences in glucocorticoid responsiveness to stress in the development of psychopathology-like behaviour and underlying neurobiology

Sophie Elizabeth Walker

EPFL2016

Differential impact of polysialyltransferase ST8SiaII and ST8iaIV knockout on social interaction and aggression

Role of the HPA axis in the long-term programming of social behaviors by peripuberty stress

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule

Implication of individual differences in glucocorticoid responsiveness to stress in the development of psychopathology-like behaviour and underlying neurobiology

Role of the HPA axis in the long-term programming of social behaviors by peripuberty stress

Implication of individual differences in glucocorticoid responsiveness to stress in the development of psychopathology-like behaviour and underlying neurobiology

Age-related cognitive impairments in mice with a conditional ablation of the neural cell adhesion molecule