Oxytocin Modifies the Excitability and the Action Potential Shape of the Hippocampal CA1 GABAergic Interneurons.

Oxytocin (OT) is a neuropeptide that modulates social-related behavior and cognition in the central nervous system of mammals. In the CA1 area of the hippocampus, the indirect effects of the OT on the pyramidal neurons and their role in information processing have been elucidated. However, limited data are available concerning the direct modulation exerted by OT on the CA1 interneurons (INs) expressing the oxytocin receptor (OTR). Here, we demonstrated that TGOT (Thr4,Gly7-oxytocin), a selective OTR agonist, affects not only the membrane potential and the firing frequency but also the neuronal excitability and the shape of the action potentials (APs) of these INs in mice. Furthermore, we constructed linear mixed-effects models (LMMs) to unravel the dependencies between the AP parameters and the firing frequency, also considering how TGOT can interact with them to strengthen or weaken these influences. Our analyses indicate that OT regulates the functionality of the CA1 GABAergic INs through different and independent mechanisms. Specifically, the increase in neuronal firing rate can be attributed to the depolarizing effect on the membrane potential and the related enhancement in cellular excitability by the peptide. In contrast, the significant changes in the AP shape are directly linked to oxytocinergic modulation. Importantly, these alterations in AP shape are not associated with the TGOT-induced increase in neuronal firing rate, being themselves critical for signal processing.

Prolonged activation of EP3 receptor-expressing preoptic neurons underlies torpor responses.

Many species use a temporary drop in body temperature and metabolic rate (torpor) as a strategy to survive food scarcity. A similar profound hypothermia is observed with activation of preoptic neurons that express the neuropeptides Pituitary Adenylate-Cyclase-Activating Polypeptide (PACAP)1, Brain Derived Neurotrophic Factor (BDNF)2, or Pyroglutamylated RFamide Peptide (QRFP)3, the vesicular glutamate transporter, Vglut24,5 or the leptin receptor6 (LepR), estrogen 1 receptor (Esr1)7 or prostaglandin E receptor 3 (EP3R) in mice8. However, most of these genetic markers are found on multiple populations of preoptic neurons and only partially overlap with one another. We report here that expression of the EP3R marks a unique population of median preoptic (MnPO) neurons that are required both for lipopolysaccharide (LPS)-induced fever9 and for torpor. These MnPOEP3R neurons produce persistent fever responses when inhibited and prolonged hypothermic responses when activated either chemo- or opto-genetically even for brief periods of time. The mechanism for these prolonged responses appears to involve increases in intracellular calcium in individual EP3R-expressing preoptic neurons that persist for many minutes up to hours beyond the termination of a brief stimulus. These properties endow MnPOEP3R neurons with the ability to act as a two-way master switch for thermoregulation.

Neuromodulatory functions exerted by oxytocin on different populations of hippocampal neurons in rodents.

Oxytocin (OT) is a neuropeptide widely known for its peripheral hormonal effects (i.e., parturition and lactation) and central neuromodulatory functions, related especially to social behavior and social, spatial, and episodic memory. The hippocampus is a key structure for these functions, it is innervated by oxytocinergic fibers, and contains OT receptors (OTRs). The hippocampal OTR distribution is not homogeneous among its subregions and types of neuronal cells, reflecting the specificity of oxytocin's modulatory action. In this review, we describe the most recent discoveries in OT/OTR signaling in the hippocampus, focusing primarily on the electrophysiological oxytocinergic modulation of the OTR-expressing hippocampal neurons. We then look at the effect this modulation has on the balance of excitation/inhibition and synaptic plasticity in each hippocampal subregion. Additionally, we review OTR downstream signaling, which underlies the OT effects observed in different types of hippocampal neuron. Overall, this review comprehensively summarizes the advancements in unraveling the neuromodulatory functions exerted by OT on specific hippocampal networks.

Membrane Resonance in Pyramidal and GABAergic Neurons of the Mouse Perirhinal Cortex.

The perirhinal cortex (PRC) is a polymodal associative region of the temporal lobe that works as a gateway between cortical areas and hippocampus. In recent years, an increasing interest arose in the role played by the PRC in learning and memory processes, such as object recognition memory, in contrast with certain forms of hippocampus-dependent spatial and episodic memory. The integrative properties of the PRC should provide all necessary resources to select and enhance the information to be propagated to and from the hippocampus. Among these properties, we explore in this paper the ability of the PRC neurons to amplify the output voltage to current input at selected frequencies, known as membrane resonance. Within cerebral circuits the resonance of a neuron operates as a filter toward inputs signals at certain frequencies to coordinate network activity in the brain by affecting the rate of neuronal firing and the precision of spike timing. Furthermore, the ability of the PRC neurons to resonate could have a fundamental role in generating subthreshold oscillations and in the selection of cortical inputs directed to the hippocampus. Here, performing whole-cell patch-clamp recordings from perirhinal pyramidal neurons and GABAergic interneurons of GAD67-GFP+ mice, we found, for the first time, that the majority of PRC neurons are resonant at their resting potential, with a resonance frequency of 0.5-1.5 Hz at 23°C and of 1.5-2.8 Hz at 36°C. In the presence of ZD7288 (blocker of HCN channels) resonance was abolished in both pyramidal neurons and interneurons, suggesting that Ih current is critically involved in resonance generation. Otherwise, application of TTx (voltage-dependent Na+ channel blocker) attenuates the resonance in pyramidal neurons but not in interneurons, suggesting that only in pyramidal neurons the persistent sodium current has an amplifying effect. These experimental results have also been confirmed by a computational model. From a functional point of view, the resonance in the PRC would affect the reverberating activity between neocortex and hippocampus, especially during slow wave sleep, and could be involved in the redistribution and strengthening of memory representation in cortical regions.