Plasticity of intrinsic excitability across the estrous cycle in hypothalamic CRH neurons.

Stress responses are highly plastic and vary across physiological states. The female estrous cycle is associated with a number of physiological changes including changes in stress responses, however, the mechanisms driving these changes are poorly understood. Corticotropin-releasing hormone (CRH) neurons are the primary neural population controlling the hypothalamic-pituitary-adrenal (HPA) axis and stress-evoked corticosterone secretion. Here we show that CRH neuron intrinsic excitability is regulated over the estrous cycle with a peak in proestrus and a nadir in estrus. Fast inactivating voltage-gated potassium channel (IA) currents showed the opposite relationship, with current density being lowest in proestrus compared to other cycle stages. Blocking IA currents equalized excitability across cycle stages revealing a role for IA in mediating plasticity in stress circuit function over the female estrous cycle.

Impact of chronic variable stress on neuroendocrine hypothalamus and pituitary in male and female C57BL/6J mice.

Chronic stress exerts multiple negative effects on the physiology and health of an individual. In the present study, we examined hypothalamic, pituitary and endocrine responses to 14 days of chronic variable stress (CVS) in male and female C57BL/6J mice. In both sexes, CVS induced a significant decrease in body weight and enhanced the acute corticosterone stress response, which was accompanied by a reduction in thymus weight only in females. However, single-point blood measurements of basal prolactin, thyroid-stimulating hormone, luteinising hormone, growth hormone and corticosterone levels taken at the end of the CVS were not different from those of controls. Similarly, pituitary mRNA expression of Fshb, Lhb, Prl and Gh was unchanged by CVS, although Pomc and Tsh were significantly elevated. Within the adrenal medulla, mRNA for Th, Vip and Gal were elevated following CVS. Avp transcript levels within the paraventricular nucleus of the hypothalamus were increased by CVS; however, levels of Gnrh1, Crh, Oxt, Sst, Trh, Ghrh, Th and Kiss1 remained unchanged. Oestrous cycles were lengthened slightly by CVS and ovarian histology revealed a reduction in the number of preovulatory follicles and corpora lutea. Taken together, these observations indicate that 14 days of CVS induces an up-regulation of the neuroendocrine stress axis and creates a mild disruption of female reproductive function. However, the lack of changes in other neuroendocrine axes controlling anterior and posterior pituitary secretion suggest that most neuroendocrine axes are relatively resilient to CVS.

Stress experience and hormone feedback tune distinct components of hypothalamic CRH neuron activity.

Stress leaves a lasting impression on an organism and reshapes future responses. However, the influence of past experience and stress hormones on the activity of neural stress circuits remains unclear. Hypothalamic corticotropin-releasing hormone (CRH) neurons orchestrate behavioral and endocrine responses to stress and are themselves highly sensitive to corticosteroid (CORT) stress hormones. Here, using in vivo optical recordings, we find that CRH neurons are rapidly activated in response to stress. CRH neuron activity robustly habituates to repeated presentations of the same, but not novel stressors. CORT feedback has little effect on CRH neuron responses to acute stress, or on habituation to repeated stressors. Rather, CORT preferentially inhibits tonic CRH neuron activity in the absence of stress stimuli. These findings reveal how stress experience and stress hormones modulate distinct components of CRH neuronal activity to mediate stress-induced adaptations.

Regulation of electrical bursting in a spatiotemporal model of a GnRH neuron.

Gonadotropin-releasing hormone (GnRH) neurons are hypothalamic neurons that control the pulsatile release of GnRH that governs fertility and reproduction in mammals. The mechanisms underlying the pulsatile release of GnRH are not well understood. Some mathematical models have been developed previously to explain different aspects of these activities, such as the properties of burst action potential firing and their associated Ca(2+) transients. These previous studies were based on experimental recordings taken from the soma of GnRH neurons. However, some research groups have shown that the dendrites of GnRH neurons play very important roles. In particular, it is now known that the site of action potential initiation in these neurons is often in the dendrite, over 100 µm from the soma. This raises an important question. Since some of the mechanisms for controlling the burst length and interburst interval are located in the soma, how can electrical bursting be controlled when initiated at a site located some distance from these controlling mechanisms? In order to answer this question, we construct a spatio-temporal mathematical model that includes both the soma and the dendrite. Our model shows that the diffusion coefficient for the spread of electrical potentials in the dendrite is large enough to coordinate burst firing of action potentials when the initiation site is located at some distance from the soma.

Cellular mechanisms preventing sustained activation of cortex during subcortical high-frequency stimulation.

Axonal excitation has been proposed as a key mechanism in therapeutic brain stimulation. In this study we examined how high-frequency stimulation (HFS) of subcortical white matter tracts projecting to motor cortex affects downstream postsynaptic responses in cortical neurons. Whole cell recordings were performed in the primary motor cortex (M1) and ventral thalamus of rat brain slices. In M1, neurons showed only an initial depolarization in response to HFS, after which the membrane potential returned to prestimulation levels. The prolonged suppression of excitation during stimulation was neither associated with GABAergic inhibition nor complete action potential failure in stimulated axons. Instead we found that HFS caused a depression of excitatory synaptic currents in postsynaptic neurons that was specific to the stimulated subcortical input. These data are consistent with the hypothesis that axonal HFS produces a functional deafferentation of postsynaptic targets likely from depletion of neurotransmitter.

Selective attenuation of afferent synaptic transmission as a mechanism of thalamic deep brain stimulation-induced tremor arrest.

Deep brain stimulation (DBS) of the ventrolateral thalamus stops several forms of tremor. Microelectrode recordings in the human thalamus have revealed tremor cells that fire synchronous with electromyographic tremor. The efficacy of DBS likely depends on its ability to modify the activity of these tremor cells either synaptically by stopping afferent tremor signals or by directly altering the intrinsic membrane currents of the neurons. To test these possibilities, whole-cell patch-clamp recordings of ventral thalamic neurons were obtained from rat brain slices. DBS was simulated (sDBS) using extracellular constant current pulse trains (125 Hz, 60-80 micros, 0.25-5 mA, 1-30 s) applied through a bipolar electrode. Using a paired-pulse protocol, we first established that thalamocortical relay neurons receive converging input from multiple independent afferent fibers. Second, although sDBS induced homosynaptic depression of EPSPs along its own pathway, it did not alter the response from a second independent pathway. Third, in contrast to the subthalamic nucleus, sDBS in the thalamus failed to inhibit the rebound potential and the persistent Na+ current but did activate the Ih current. Finally, in eight patients undergoing thalamic DBS surgery for essential tremor, microstimulation was most effective in alleviating tremor when applied in close proximity to recorded tremor cells. However, stimulation could still suppress tremor at distances incapable of directly spreading to recorded tremor cells. These complementary data indicate that DBS may induce a "functional deafferentation" of afferent axons to thalamic tremor cells, thereby preventing tremor signal propagation in humans.