The functional neuroanatomy of helplessness vulnerability

This dissertation had three specific aims: 1) to behaviorally characterize the congenital helplessness rat model of vulnerability to depression and post-traumatic stress disorder (PTSD); 2) to metabolically map the brains of naïve congenitally helpless adults and newborns; and 3) to map the effects of the antidepressant fluoxetine on the brains of these rats. Congenitally helpless rats, selectively bred for vulnerability to learned helplessness, were assessed on tests of exploratory activity, anxiety, circadian activity, and interest in reward; they showed increased exploration and reduced anxiety in novel environments, but also insomnia and reduced sucrose preference. This pattern of results is discussed as resembling the temperamental profile of individuals with PTSD. The brains of rats from the congenitally helpless strain were metabolically mapped with quantitative cytochrome oxidase histochemistry. Adults showed widespread metabolic abnormalities in several brain regions, but these abnormalities were bidirectional and whole-brain metabolism was not altered; the paraventricular hypothalamic nucleus (PVH), habenula, ventral hippocampus, interpeduncular nucleus, and infralimbic cortex showed increases, and the dorsomedial prefrontal cortex, basal ganglia, septal nuclei, amygdala, and ventral tegmental area (VTA) showed decreases. In contrast, newborns showed a global reduction in brain metabolism, but the largest decreases were seen in the two regions showing the largest increases in the adult: the PVH and habenula. Newborns also showed a marked reduction in interregional functional coupling, particularly between forebrain and brainstem regions. Fluoxetine produced anti-depressant effects in the adult brain, increasing VTA metabolism and decreasing habenula metabolism. Thus, the only common region affected in adults and newborns and by fluoxetine treatment was the habenula. Functional relationships among the implicated brain systems were considered in light of the literature on depression and PTSD. It is suggested that the hypometabolism and absence of functional connectivity observed in the newborn may reflect reduced ability of forebrain regions to regulate the response of brainstem regions to stress. Consequently, the PVH may become hyperactive in the adult, and other regions may follow suit in an unsuccessful attempt to constrain its activity. The habenula is discussed as a possible nexus through which antidepressants may influence stress-responsive networks.