The paraventricular nucleus of the hypothalamus - a potential target for integrative treatment of autonomic dysfunction

Abstract

Background: The paraventricular nucleus of the hypothalamus (PVN) has emerged as one of the most important autonomic control centers in the brain, with neurons playing essential roles in controlling stress, metabolism, growth, reproduction, immune and other more traditional autonomic functions (gastrointestinal, renal and cardiovascular).

Objectives: Traditionally the PVN was viewed as a nucleus in which afferent inputs from other regions were faithfully translated into changes in single specific outputs, whether neuroendocrine or autonomic. Here we present data which suggest that the PVN plays significant and essential roles in integrating multiple sources of afferent input and sculpting an integrated autonomic output by concurrently modifying the excitability of multiple output pathways. In addition, we highlight recent work that suggests that dysfunction of such intranuclear integrative circuitry contributes to the pathology of conditions such as hypertension and congestive heart failure.

Conclusions: This review highlights data showing that individual afferent inputs (subfornical organ), signaling molecules (orexins, adiponectin), and interneurons (glutamate/GABA), all have the potential to influence (and thus coordinate) multiple PVN output pathways. We also highlight recent studies showing that modifications in this integrated circuitry may play significant roles in the pathology of diseases such as congestive heart failure and hypertension.

Figure 1

This schematic illustrates the classical view of the organization of the paraventricular nucleus of the hypothalamus. Afferent inputs originating from diverse regions of the CNS make synaptic contacts with one of the three primary functional groups of output neurons of the nucleus. The magnocellular neurons which synthesize and release vasopressin (AVP) or oxytocin (OXY) have been electrophysiologically characterized by the distinctive delayed return to baseline (see highlighted region in inset) following a depolarizing pulse which indicates the presence of a dominant transient potassium conductance known as I_A. In contrast the parvocellular preautonomic neurons which project to autonomic control centers of the medulla and spinal cord are characterized by a different electrophysiological fingerprint manifested by a low threshold calcium spike (see highlighted region in inset) following such depolarizing pulses which is the result of activation of a T-type calcium conductance in this subpopulation of neurons. Finally the parvocellular neuroendocrine cells, which express neither of these conductances, synthesize CRH and TRH (as well as other factors), project to the median eminence, where they release these hypophysiotropic factors into the hypophysial portal circulation.

Figure 2

This schematic illustrates modifications to the classical view of the organization of the paraventricular nucleus of the hypothalamus associated with recent work identifying important roles for both glutamate and GABA interneurons in controlling the excitability of magnocellular and parvocellular output neurons.

Figure 3

This schematic illustrates our current understanding of the multiple mechanisms through which ANG influences the excitability of magnocellular, parvocellular neuroendocrine and parvocellular preautonomic neurons in the paraventricular nucleus of the hypothalamus. In magnocellular neurons ANG has direct effects to inhibit a transient potassium conductance I_A, and indirect depolarizing effects resulting from the activation of glutamate interneurons. In addition the ANG mediated activation of these neurons appears to be held in check by the subsequent production of nitric oxide which in turn activates a short loop inhibitory feedback pathway as a consequence of nitric oxide actions on GABA interneurons in the halo zone surrounding the nucleus. In contrast ANG appears to depolarize parvocellular neuroendocrine cells as a result of direct modulation of both a non selective cationic conductance and a sustained potassium conductance (likely IK), again with such activation likely activating NO/GABA feedback circuits. Finally, although there is no definitive evidence identifying ion channels regulated by ANG in PVN preautonomic neurons, effects have been shown to be AT₁ receptor mediated and again appear to activate NO/GABA feedback loops, dysfunction of which have been implicated in congestive heart failure and hypertension.