When worry may be good for you: Worry severity and limbic-prefrontal functional connectivity in late-life generalized anxiety disorder.

BACKGROUND: Late-life generalized anxiety disorder (GAD) is one of the most common anxiety disorders in older adults. However, its neural markers have received relatively little attention. In this study, we explored the association between worry severity and limbic-prefrontal connectivity during emotional reactivity in late-life GAD. METHODS: We recruited 16 anxious (GAD) and 20 non-anxious (HC) older adults to perform the faces/shapes emotional reactivity task during functional magnetic resonance imaging (fMRI). We investigated the functional connectivity of both the amygdala and the bed nucleus of stria terminalis (BNST) with the prefrontal cortex (PFC) using generalized psychophysiological interaction (gPPI) analysis. We tested for (1) group differences in connectivity, (2) association between worry severity and connectivity, and (3) interaction between group and worry severity and its association with connectivity. RESULTS: Amygdala-PFC and BNST-PFC functional connectivity were associated with worry severity in an inverse U-shape, and was independent of depression severity, global anxiety, neuroticism, and general cognitive function. LIMITATIONS: Our limitations include slightly skewed PSWQ distributions, lack of non-anxious individuals with high worry, small sample size, and low depression comorbidity in a sample of late-life GAD that may not generalize to GAD in younger populations. CONCLUSIONS: This suggests that moderate worry is associated with maximum engagement of the limbic-PFC connectivity, while severe worry is associated with failure of the limbic-PFC emotional regulation circuit. This may explain the aberrant and exaggerated responses to negative stimuli observed in participants with pathological worry.

Central neural responses to restraint stress are altered in rats with an early life history of repeated brief maternal separation.

Repeated brief maternal separation (i.e. 15 min daily, MS15) of rat pups during the first one to two postnatal weeks enhances active maternal care received by the pups and attenuates their later behavioral and neuroendocrine responses to stress. In previous work, we found that MS15 also alters the developmental assembly and later structure of central neural circuits that control autonomic outflow to the viscera, suggesting that MS15 may alter central visceral circuit responses to stress. To examine this, juvenile rats with a developmental history of either MS15 or no separation (NS) received microinjection of retrograde neural tracer, FluoroGold (FG), into the hindbrain dorsal vagal complex (DVC). After 1 week, FG-injected rats and surgically intact littermates were exposed to either a 15-min restraint stress or an unrestrained control condition, and then perfused 1 h later. Brain tissue sections from surgically intact littermates were processed for Fos alone or in combination with phenotypic markers to examine stress-induced activation of neurons within the paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST), and hindbrain DVC. Compared to NS controls, MS15 rats displayed less restraint-induced Fos activation within the dorsolateral BNST (dBNST), the caudal PVN, and noradrenergic neurons within the caudal DVC. To examine whether these differences corresponded with altered neural inputs to the DVC, sections from tracer-injected rats were double-labeled for FG and Fos to quantify retrogradely labeled neurons within hypothalamic and limbic forebrain regions of interest, and the proportion of these neurons activated after restraint. Only the dBNST displayed a significant effect of postnatal experience on restraint-induced Fos activation of DVC-projecting neurons. The distinct regional effects of MS15 on stress-induced recruitment of neurons within hypothalamic, limbic forebrain, and hindbrain regions has interesting implications for understanding how early life experience shapes the functional organization of stress-responsive circuits.

Repeated brief postnatal maternal separation enhances hypothalamic gastric autonomic circuits in juvenile rats.

Maternal separation of rat pups for 15 min each day over the first one to two postnatal weeks (MS15) has been shown to increase the active maternal care received by pups and to decrease their later neuroendocrine and behavioral stress reactivity compared to non-separated (NS) controls. Stress responses prominently feature altered gastric secretion and motility, and we previously reported that the developmental assembly of forebrain circuits underlying gastric autonomic control, including gastric responses to stress, is delayed by MS15 in neonatal rats [Card JP, Levitt P, Gluhovsky M, Rinaman L (2005) J Neurosci 25(40):9102-9111]. To determine how this early delay affects the later organization of central gastric autonomic circuits, the present study examined the effects of neonatal MS15 on central pre-gastric circuits assessed in post-weaning, juvenile rats. For this purpose, the retrograde transynaptic viral tracer, pseudorabies virus (PRV), was microinjected into the stomach wall of 28-30 day old male rats with an earlier developmental history of either MS15 or NS. Rats were perfused 72 h later and tissue was processed to reveal PRV-positive cells. Transynaptic PRV immunolabeling was quantified in selected preautonomic brainstem and forebrain regions, including the area postrema, bed nucleus of the stria terminalis, central nucleus of the amygdala, paraventricular nucleus of the hypothalamus (PVN), and visceral cortices. Compared to NS controls, MS15 rats displayed a significantly greater amount of PRV labeling within the PVN, including both the dorsal cap and ventral subnuclei. There were no postnatal group differences in the amount of PRV labeling within any other brain region examined in this study. This effect of MS15 to enhance hypothalamic preautonomic circuit structure indicates a strengthening of this pathway and may provide insight into how early life experience produces differential effects on later stress reactivity, including gastric secretory and motor responses to stress.