Helmer F. Figueiredo

The medial prefrontal cortex differentially regulates stress‐induced c‐fos expression in the forebrain depending on type of stressor

The medial prefrontal cortex (mPFC) plays an important inhibitory role in the hypothalamic‐pituitary‐adrenal (HPA) axis response. The involvement of the mPFC appears to depend on the type of stressor, preferentially affecting ‘psychogenic’ stimuli. In this study, we mapped expression of c‐fos mRNA to assess the neural circuitry underlying stressor‐specific actions of the mPFC on HPA reactivity. Thus, groups of mPFC‐lesioned and sham‐operated rats were restrained for 20 min or exposed to ether fumes for 2 min. In both cases, the animals were killed at 40 min from the onset of stress. Interestingly, bilateral lesions of the mPFC significantly enhanced c‐fos mRNA expression in the hypothalamic paraventricular nucleus of restrained animals, an effect that was paralleled by potentiation of circulating ACTH concentrations in these animals. On the other hand, lesions of the mPFC did not affect neither PVN c‐fos mRNA expression nor plasma ACTH concentrations in animals exposed to ether. Lesions of the mPFC also enhanced c‐fos activation in the medial amygdala following restraint, but not following ether exposure. Additional regions whose activity was affected by mPFC lesions or stressor differences included the ventrolateral division of the bed nucleus of the stria terminalis, CA3 hippocampus, piriform cortex, and dorsal endopiriform nucleus. Expression of c‐fos mRNA was nearly absent in the central amygdala of all stressed animals, regardless of lesion. Furthermore, prefrontal cortex lesions did not change stress‐induction levels of c‐fos in the CA1 hippocampus, dentate gyrus, anteromedial division of the bed nucleus of the stria terminalis, lateral septum, and claustrum. Taken together, this study indicates that the medial prefrontal cortex differentially regulates cellular activation of specific stress‐related brain regions, thus exerting stressor‐dependent inhibition of the HPA axis.

Role of GABA and Glutamate Circuitry in Hypothalamo‐Pituitary‐Adrenocortical Stress Integration

Abstract: GABA and glutamate play a major role in central integration of hypothalamo‐pituitary‐adrenocortical (HPA) stress responses. Recent work in our group has focused on mechanisms whereby GABAergic and glutamatergic circuits interact with parvocellular paraventricular nucleus (PVN) neurons controlling the HPA axis. GABAergic neurons in the bed nucleus of the stria terminalis, preoptic area, and hypothalamus can directly inhibit PVN outflow and thereby reduce ACTH secretion. In contrast, glutamate activates the HPA axis, presumably by way of hypothalamic and brainstem projections to the PVN. These inhibitory and excitatory PVN‐projecting neurons are controlled by descending information from limbic forebrain structures, including glutamatergic neurons of the ventral subiculum, prefrontal cortex, and GABAergic cells from the amygdala and perhaps septum. Lesion studies indicate that the ventral subiculum and prefrontal cortex are involved in inhibition of HPA axis responses to psychogenic stimuli, whereas the amygdala is positioned to enhance hormone secretion by way of GABA‐GABA disinhibitory connections. Thus, it seems the psychogenic responses to stress are gated by discrete sets of GABAergic neurons in the basal forebrain and hypothalamus. As such, these neurons are positioned to summate limbic inputs into net inhibitory tone on the PVN and may thus play a major role in HPA dysfunction seen in affective disease states and aging.

Chapter 4.1 – Neurocircuit regulation of the hypothalamo–pituitary–adrenocortical stress response – an overview

Abstract: Central integration of the hypothalamo–pituitary–adrenocortical (HPA) axis stress response is controlled by neurosecretory neurons in the medial parvocellular paraventricular nucleus (PVN). Activation of the PVN is a complex process regulated by both direct and indirect neuronal connections, as well as communication with blood-borne messengers. Ascending brainstem pathways from the nucleus of the solitary tract (both catecholaminergic and noncatecholaminergic systems) and serotonergic midbrain raphe nuclei provide direct neuronal excitation of PVN neurons. Stimulation of the HPA axis is also mediated by transsynaptic inputs from the medial and central amygdaloid nuclei, which disinhibit the PVN by way of GABAergic relay neurons in the hypothalamus and bed nucleus of the stria terminalis (BST), and perhaps enhance excitatory input from the brainstem. Inhibition of the HPA axis is controlled by PVN-projecting GABA neurons in the hypothalamus and BST, which are driven in part by descending stimulatory inputs from ventral subiculum and infralimbic cortex. The PVN is profoundly affected by blood-borne factors (including peptides and cytokines); these messengers communicate with the PVN through interactions with circumventricular organs or by induction of perivascular prostaglandin synthesis. Finally, glucocorticoids can directly inhibit PVN neurons, by diffusion from the dense vascular beds localized in this region. Thus, activation of the HPA axis is controlled by a wide variety of signals from both brain and periphery, which are thence effectively integrated into a net secretory signal at the level of the hypophysiotrophic PVN neuron.