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The rostral hypothalamus, especially the preoptic-anterior hypothalamus (POAH), contains temperature-sensitive and -insensitive neurons that form synaptic networks to control thermoregulatory responses. Previous studies suggest that the cyclic nucleotide cGMP is an important mediator in this neuronal network, since hypothalamic microinjections of cGMP analogs produce hypothermia in several species. In the present study, immunohistochemisty showed that rostral hypothalamic neurons contain cGMP, guanylate cyclase (necessary for cGMP synthesis), and CNG A2 (an important cyclic nucleotide-gated channel). Extracellular electrophysiological activity was recorded from different types of neurons in rat hypothalamic tissue slices. Each recorded neuron was classified according to its thermosensitivity as well as its firing rate response to 2-100 microM 8-bromo-cGMP (a membrane-permeable cGMP analog). cGMP has specific effects on different neurons in the rostral hypothalamus. In the POAH, the cGMP analog decreased the spontaneous firing rate in 45% of temperature-sensitive and -insensitive neurons, an effect that is likely due to cGMP-enhanced hyperpolarizing K(+) currents. This decreased POAH activity could attenuate thermoregulatory responses and produce hypothermia during exposures to cool or neutral ambient temperatures. Although 8-bromo-cGMP did not affect the thermosensitivity of most POAH neurons, it did increase the warm sensitivity of neurons in other hypothalamic regions located dorsal, lateral, and posterior to the POAH. This increased thermosensitivity may be due to pacemaker currents that are facilitated by cyclic nucleotides. If some of these non-POAH thermosensitive neurons promote heat loss or inhibit heat production, then their increased thermosensitivity could contribute to cGMP-induced decreases in body temperature.

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The preoptic-anterior hypothalamus (POAH) controls body temperature, and thermoregulatory responses are impaired during hypercapnia. If increased CO(2) or its accompanying acidosis inhibits warm-sensitive POAH neurons, this could provide an explanation for thermoregulatory impairment during hypercapnia. To test this possibility, extracellular electrophysiological recordings determined the effects of CO(2) and pH on the firing rates of both temperature-sensitive and -insensitive neurons in hypothalamic tissue slices from 89 male Sprague-Dawley rats. Firing rate activity was recorded in 121 hypothalamic neurons before, during, and after changing the CO(2) concentration aerating the tissue slice chamber or changing the pH of the solution bathing the tissue slices. Increasing the aeration CO(2) concentration from 5% (control) to 10% (hypercapnic) had no effect on most (i.e., 69%) POAH temperature-insensitive neurons; however, this hypercapnia inhibited the majority (i.e., 59%) of warm-sensitive neurons. CO(2) affected similar proportions of (non-POAH) neurons in other hypothalamic regions. These CO(2) effects appear to be due to changes in pH since the CO(2)-affected neurons responded similarly to isocapnic acidosis (i.e., normal CO(2) and decreased pH) but were not responsive to isohydric hypercapnia (i.e., increased CO(2) and normal pH). These findings may offer a neural explanation for some heat-related illnesses (e.g., exertional heat stroke) where impaired heat loss is associated with acidosis.

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Thermoregulatory responses are partially controlled by the preoptic area and anterior hypothalamus (PO/AH), which contains a mixed population of temperature-sensitive and insensitive neurons. Immunohistochemical procedures identified the extent of various ionic channels in rat PO/AH neurons. These included pacemaker current channels [i.e., hyperpolarization-activated cyclic nucleotide-gated channels (HCN)], background potassium leak channels (TASK-1 and TRAAK), and transient receptor potential channel (TRP) TRPV4. PO/AH neurons showed dense TASK-1 and HCN-2 immunoreactivity and moderate TRAAK and HCN-4 immunoreactivity. In contrast, the neuronal cell bodies did not label for TRPV4, but instead, punctate labeling was observed in traversing axons or their terminal endings. On the basis of these results and previous electrophysiological studies, Hodgkin-Huxley-like models were constructed. These models suggest that most PO/AH neurons have the same types of ionic channels, but different levels of channel expression can explain the inherent properties of the various types of temperature-sensitive and insensitive neurons.

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In 1965, H. T. Hammel proposed a neuronal model to explain set-point thermoregulation. His model was based on a synaptic network encompassing four different types of hypothalamic neurons: i.e., warm-sensitive and temperature-insensitive neurons and heat loss and heat production effector neurons. Although some modifications to this model are suggested, recent electrophysiological and morphological studies support many of the model's major tenets. Hypothalamic warm-sensitive neurons integrate core and peripheral thermal information. These neurons sense changes in hypothalamic temperature, and they orient their dendrites medially and laterally to receive ascending afferent input from cutaneous thermoreceptors. Temperature-insensitive neurons have a different dendritic orientation and may provide constant reference signals, which are important in determining thermoregulatory set points. In Hammel's model, temperature-sensitive and -insensitive neurons send mutually antagonistic synaptic inputs to effector neurons controlling various thermoregulatory responses. The model predicts that warm-sensitive neurons synaptically excite heat loss effector neurons and inhibit heat production effector neurons. In recent studies, one counterpart of these effector neurons may be "excitatory postsynaptic potential-driven neurons," the activity of which is dependent on synaptic excitation from nearby cells. Excitatory postsynaptic potential-driven neurons have sparse dendrites that appear to be specifically oriented, either medially or laterally, presumably to receive selective synaptic input from a discrete source. Another counterpart of effector neurons may be "silent neurons," which have extensive dendritic branches that may receive synaptic excitation from remote sources. Because some silent neurons receive synaptic inhibition from nearby warm-sensitive neurons, Hammel's model would predict that they have a role in heat production or heat retention responses.

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Preoptic-anterior hypothalamic (PO/AH) neurones sense and regulate body temperature. Although controversial, it has been postulated that warm-induced depolarization determines neuronal thermosensitivity. Supporting this hypothesis, recent studies suggest that temperature-sensitive cationic channels (e.g. vanilloid receptor TRP channels) constitute the underlying mechanism of neuronal thermosensitivity. Moreover, earlier studies indicated that PO/AH neuronal warm sensitivity is due to depolarizing sodium currents that are sensitive to tetrodotoxin (TTX). To test these possibilities, intracellular recordings were made in rat hypothalamic tissue slices. Thermal effects on membrane potentials and currents were compared in PO/AH warm-sensitive, temperature-insensitive and silent neurones. All three types of neurones displayed slight depolarization during warming and hyperpolarization during cooling. There were no significant differences in membrane potential thermosensitivity for the different neuronal types. Voltage clamp recordings (at -92 mV) measured the thermal effects on persistent inward cationic currents. In all neurones, resting holding currents decreased during cooling and increased during warming, and there was no correlation between firing rate thermosensitivity and current thermosensitivity. To determine the thermosensitive contribution of persistent, TTX-sensitive currents, voltage clamp recordings were conducted in the presence of 0.5 microm TTX. TTX decreased the current thermosensitivity in most neurones, but there were no resulting differences between the different neuronal types. The present study found no evidence of a resting ionic current that is unique to warm-sensitive neurones. This supports studies suggesting that neuronal thermosensitivity is controlled, not by resting currents, but rather by currents that determine rapid changes in membrane potential between successive action potentials.

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