Male-specific deficits in natural reward learning in a mouse model of neurodevelopmental disorders.

Neurodevelopmental disorders, including autism spectrum disorders, are highly male biased, but the underpinnings of this are unknown. Striatal dysfunction has been strongly implicated in the pathophysiology of neurodevelopmental disorders, raising the question of whether there are sex differences in how the striatum is impacted by genetic risk factors linked to neurodevelopmental disorders. Here we report male-specific deficits in striatal function important to reward learning in a mouse model of 16p11.2 hemideletion, a genetic mutation that is strongly associated with the risk of neurodevelopmental disorders, particularly autism and attention-deficit hyperactivity disorder. We find that male, but not female, 16p11.2 deletion animals show impairments in reward-directed learning and maintaining motivation to work for rewards. Male, but not female, deletion animals overexpress mRNA for dopamine receptor 2 and adenosine receptor 2a in the striatum, markers of medium spiny neurons signaling via the indirect pathway, associated with behavioral inhibition. Both sexes show a 50% reduction of mRNA levels of the genes located within the 16p11.2 region in the striatum, including the kinase extracellular-signal related kinase 1 (ERK1). However, hemideletion males show increased activation in the striatum for ERK1, both at baseline and in response to sucrose, a signaling change associated with decreased striatal plasticity. This increase in ERK1 phosphorylation is coupled with a decrease in the abundance of the ERK phosphatase striatum-enriched protein-tyrosine phosphatase in hemideletion males. In contrast, females do not show activation of ERK1 in response to sucrose, but notably hemideletion females show elevated protein levels for ERK1 as well as the related kinase ERK2 over what would be predicted by mRNA levels. These data indicate profound sex differences in the impact of a genetic lesion linked with neurodevelopmental disorders, including mechanisms of male-specific vulnerability and female-specific resilience impacting intracellular signaling in the brain.

The hypothalamic transcriptional response to stress is severely impaired in offspring exposed to adverse nutrition during gestation.

Gestation is a time of profound vulnerability, as insults during pregnancy increase the lifelong risk of morbidity for the offspring. Increasingly, maternal diet is recognized as a key factor influencing the developing fetus. Poor-quality maternal diets, whether they provide an excess or an insufficiency of nutrients, lead to overt gestational growth disturbances in the offspring, and elevated risk for a common cluster of metabolic and mental disorders. Metabolic disturbances, particularly a substantially increased risk of obesity, have been linked in both maternal overnutrition and maternal undernutrition with abnormal development of the offspring hypothalamus, which serves a vital role in the central regulation of feeding. Additionally, the hypothalamus also coordinates physiological responses to stressors, and may thus play a role in vulnerability to psychiatric disease in these offspring. We examined hypothalamic molecular and endocrine responses to a psychological stressor (restraint) and a physiological stressor (lipopolysaccharide; LPS) in adult offspring from dams fed a high-fat diet or a low-protein diet during gestation and lactation. Targeted gene expression in the hypothalamus for 26 genes of interest sorted via hierarchical clustering revealed that the vast majority of these transcripts were substantially upregulated by both stressors. In contrast, offspring of maternal high-fat and low-protein diets mounted essentially no gene expression response to either stressor. However, male and female offspring of all conditions showed elevated hypothalamic-pituitary-adrenal glucocorticoid responses to both stressors, though the recovery of corticosterone responses after stress termination was significantly impaired in offspring of poor-quality maternal diets. Overall, it appears that the ability of the hypothalamus to respond in the immediate aftermath of stressful experiences is severely impaired in offspring of poor-quality maternal diets, regardless of whether the diet provided insufficient nutrients or excessive nutrients.

The basolateral amygdala regulates adaptation to stress via ß-adrenergic receptor-mediated reductions in phosphorylated extracellular signal-regulated kinase.

The reactivity of physiological systems and behavior to psychological stress is reduced with increasing familiarity with a repeated stressor. This reduced reactivity, termed habituation, is a crucial adaptation limiting negative health consequences of stress and can be disrupted in psychopathology. We hypothesized that the ability to habituate physiologically and behaviorally to previously experienced stressors depends on ß-adrenergic receptor activation (ß-AR) in the basolateral amygdala (BLA), a specific neural substrate important for the consolidation of multiple types of memories. We observed that administration of the ß-AR antagonist propranolol into the BLA after each of four daily exposures to restraint stress prevented the normal development of neuroendocrine and behavioral habituation measured during the fifth restraint in adult male rats. In contrast, the ß-AR agonist clenbuterol administered into the BLA after each restraint on days 1-4 enhanced neuroendocrine habituation at the lowest dose but attenuated behavioral habituation at high doses. We then explored intracellular signaling mechanisms in the BLA that might be a target of ß-AR activation during stress. ß-AR activation post restraint is necessary for the alteration in basal phosphorylated ERK (pERK) levels, as daily post-stress ß-AR blockade on days 1-4 prevented repeated stress from leading to decreased pERK in the BLA on day 5. Finally, we examined the effect of blocking ERK phosphorylation in the BLA after each restraint on days 1-4 with the MEK (MAPK/ERK kinase) inhibitor U0126, and found that this was sufficient to both mimic neuroendocrine habituation in stress-naive animals and to enhance it in repeatedly stressed animals during restraint on day 5. Together, the results suggest that an individual's ability to habituate to repeated stress is regulated by activation of BLA ß-AR, which may have these effects by transducing subsequent reductions in pERK. Individual variations in ß-AR activation and intracellular signaling in the BLA may contribute significantly to adaptation to psychological stress and consequent resilience to stress-related psychopathology.