Anxiety disorders, depression and animal models of vulnerability to a depression-like syndrome have been associated with dysregulation of brain serotonergic systems. These effects could result from genetic influences, adverse early life experiences (ELE), or acute stressful life events, all of which can alter serotonergic neurotransmission and have been implicated in determining vulnerability to neuropsychiatric disorders. To evaluate the effects of ELE, adverse experiences during adulthood, and potential interactions between these factors on neuronal tryptophan hydroxylase 2 (tph2) mRNA expression, we investigated in rats the effects of maternal separation (MS)(separation from the dam for 180 min/day from postnatal day 2-14; MS180, a model of vulnerability to a depression-like syndrome), neonatal handling (separation from the dam for 15 min/day from postnatal day 2-14; MS15, a model of decreased stress sensitivity), or normal animal facility rearing (AFR) control conditions, with or without subsequent exposure to adult social defeat, on tph2 mRNA expression in the dorsal raphe nucleus (DR). Among rats exposed to social defeat, MS180 rats had increased tph2 mRNA expression in the DR, while MS15 rats had decreased tph2 mRNA expression compared to AFR rats. Social defeat increased tph2 mRNA expression, but only in MS180 rats and only in the "lateral wings" of the DR, a subdivision of the DR that is part of a sympathomotor command center. Overall, these data demonstrate that ELE and stressful experience during adulthood interact to determine tph2 mRNA expression. These changes in tph2 mRNA expression represent a potential mechanism through which adverse ELEs and stressful life experiences during adulthood may interact to increase vulnerability to stress-related psychiatric disease.

The role of central orexin in the sympathetic control of interscapular brown adipose tissue (iBAT) thermogenesis has been established in rodents. Stimulatory doses of caffeine activate orexin positive neurons in the lateral hypothalamus, a region of the brain implicated in stimulating BAT thermogenesis. This study tests the hypothesis that central administration of caffeine is sufficient to activate BAT. Low doses of caffeine administered either systemically (intravenous [IV]; 10 mg/kg) and centrally (intracerebroventricular [ICV]; 5-10 μg) increases BAT thermogenesis, in anaesthetised (1.5 g/kg urethane, IV) free breathing male rats. Cardiovascular function was monitored via an indwelling intra-arterial cannula and exhibited no response to the caffeine. Core temperature did not significantly differ after administration of caffeine via either route of administration. Caffeine administered both IV and ICV increased neuronal activity, as measured by c-Fos-immunoreactivity within subregions of the hypothalamic area, previously implicated in regulating BAT thermogenesis. Significantly, there appears to be no neural anxiety response to the low dose of caffeine as indicated by no change in activity in the basolateral amygdala. Having measured the physiological correlate of thermogenesis (heat production) we have not measured indirect molecular correlates of BAT activation. Nevertheless, our results demonstrate that caffeine, at stimulatory doses, acting via the central nervous system can increase thermogenesis, without adverse cardio-dynamic impact.