Vulnerability in early life to changes in the rearing environment plays a crucial role in the aetiopathology of psychiatric disorders

Abstract

Adverse events early in life, including maternal separation and social isolation, profoundly affect brain development and adult behaviour and may contribute to the occurrence of psychiatric disorders such as schizophrenia and mood disorders in genetically predisposed individuals. The molecular mechanisms underlying these environmentally induced developmental adaptations are unclear and best evaluated in animal paradigms with translational salience. In this study, we examined the effects in mice of maternal separation and/or social isolation for 6 h/d between postnatal days 15 and 21 on performance during adulthood in the open-field, social interaction, elevated plus-maze, forced swimming, Y-maze, novel object recognition, conditioned fear-learning, prepulse inhibition, and locomotor activity tests, to investigate whether this animal model could show the phenotypes for schizophrenia and mood disorders. The stress of maternal separation and isolation led to adult behavioural deficits, activation of the hypothalamic-pituitary-adrenal axis, and decreases in the levels of norepinephrine and dopamine in the frontal cortex and metabolites of dopamine and serotonin in the amygdala, showing the involvement of endocrine and neuronal risk in behavioural deficits. The results suggest that the frontal cortex and amygdala undergo structural remodelling induced by the stress of maternal separation and isolation, which alters behavioural and physiological responses in adulthood, including anxiety, memory and other cognitive processes. Further, social isolation enhanced the behavioural dysfunctions induced by maternal separation. These findings indicate that maternal separation and social isolation early in life can lead to long-lasting abnormal behaviour and pathophysiological impairments including schizophrenia and mood disorders.

HDAC1 links early life stress to schizophrenia-like phenotypes

“…Thus, we hypothesized that ELS might increase Hdac1 expression. To induce ELS, we subjected mice to an adapted maternal separation paradigm (hereafter simply referred to as ELS) (28) and performed behavior testing when animals were 4 mo old [postnatal day 120 (PND120)]. Mice that did not undergo the ELS protocol were used as a control group.…”

“…Maternal separation (ELS) was performed according to a recent protocol published by Niwa et al (28). In brief, the mothers were removed from the cage and the pups were subsequently placed in a Petri dish filled with bedding.…”

The Role of the Amygdala in Anxiety Disorders

“…Table 2 summarizes such studies directly manipulating 5-HT levels or 5-HT receptor activity in the amygdala. When 5-HT or 5-HT activity is decreased in the entire amygdala [145,146], a consistent increase in anxiety-like behavior is observed (Table 2). This would suggest that increased 5-HT activity in the amygdala would thus be associated with decreased anxiety, implying an anxiolytic role of 5-HT.…”

The Role of Norepinephrine in Amygdala Dependent Fear Learning and Memory

“…An increase in NE content within the amygdala modulates multiple physiological functions. In the amygdala the content of NE is higher than DA, but comparable to that of serotonin (Niwa et al, 2011). The noradrenergic neurons are present in the LC and amygdala.…”

“…The combination of latter factors in mice between postnatal day 15 (P15) and P21 reduced the social interaction time by two-fold, measured during adulthood (Niwa et al, 2011). Thus, these mice were more anxious and show a decreased short-term memory (STM) compared to the control group, which is improved with antipsychotic drug clozapine.…”