eNeuro最新文献

Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, and people with TLE exhibit higher rates of reproductive endocrine dysfunction. Hypothalamic gonadotropin-releasing hormone (GnRH) neurons regulate reproductive function in mammals by regulating gonadotropin secretion from the anterior pituitary. Previous research demonstrated GnRH neuron hyperexcitability in both sexes in the intrahippocampal kainic acid (IHKA) mouse model of TLE. Fast-inactivating A-type (I _A) and delayed rectifier K-type (I _K) K⁺ currents play critical roles in modulating neuronal excitability, including in GnRH neurons. Here, we tested the hypothesis that GnRH neuron hyperexcitability is associated with reduced I _A and I _K conductances. At 2 months after IHKA or control saline injection, when IHKA mice exhibit chronic epilepsy, we recorded GnRH neuron excitability, I _A, and I _K using whole-cell patch-clamp electrophysiology. GnRH neurons from both IHKA male and diestrus female GnRH-GFP mice exhibited hyperexcitability compared with controls. In IHKA males, although maximum I _A current density was increased, I _K recovery from inactivation was significantly slower, consistent with a hyperexcitability phenotype. In IHKA females, however, both I _A and I _K were unchanged. Sex differences were not observed in I _A or I _K properties in controls, but IHKA mice exhibited sex effects in I _A properties. These results indicate that although the emergent phenotype of increased GnRH neuron excitability is similar in IHKA males and diestrus females, the underlying mechanisms are distinct. This study thus highlights sex-specific changes in voltage-gated K⁺ currents in GnRH neurons in a mouse model of TLE and suggesting potential sex differences in GnRH neuron ion channel properties.

Each olfactory cortical hemisphere receives ipsilateral odor information directly from the olfactory bulb and contralateral information indirectly from the other cortical hemisphere. Since neural projections to the olfactory cortex are disordered and non-topographic, spatial information cannot be used to align projections from the two sides like in the visual cortex. Therefore, how bilateral information is integrated in individual cortical neurons is unknown. We have found, in mice, that the odor responses of individual neurons to selective stimulation of each of the two nostrils are significantly correlated, such that odor identity decoding optimized with information arriving from one nostril transfers very well to the other side. Nevertheless, these aligned responses are asymmetric enough to allow decoding of stimulus laterality. Computational analysis shows that such matched odor tuning is incompatible with purely random connections but is explained readily by Hebbian plasticity structuring bilateral connectivity. Our data reveal that despite the distributed and fragmented sensory representation in the olfactory cortex, odor information across the two hemispheres is highly coordinated.Significance statement Like other sense organs, animals typically have two nostrils, but how odor information from the two sides is combined to build bilateral olfactory representations remains largely unknown. Grimaud et al. find that the responses of neurons in the olfactory cortex in awake mice to odors presented separately to the ipsilateral or contralateral nostril are significantly correlated, beyond chance. Such aligned responses could arise from Hebbian plasticity in interhemispheric connections that relies on common odor experiences across the two nostrils. While responses are correlated, the remaining asymmetries in responses to the two nostrils allowed decoding of stimulus laterality. This study points to unexpected order in an olfactory circuit and prompts future work on how olfactory experience can shape interhemispheric information integration.

Neuroinflammation can lead to chronic maladaptive pain affecting millions of people worldwide. Neurotransmitters, cytokines, and ion channels are implicated in neuro-immune cell signaling but their roles in specific behavioral responses are not fully elucidated. Voltage-gated Ca_V2.2 channel activity in skin controls rapid and transient heat hypersensitivity induced by intradermal (id) capsaicin via IL-1α cytokine signaling. Ca_V2.2 channels are not, however, involved in mechanical hypersensitivity that developed in the id capsaicin animal model. Here, we show that Ca_V2.2 channels are also critical for heat hypersensitivity induced by id Complete Freund's Adjuvant (CFA). Id CFA, a model of chronic neuroinflammation, involves ongoing cytokine signaling for days leading to pronounced edema and hypersensitivity to sensory stimuli. Peripheral Ca_V2.2 channel activity in skin was required for the full development and week-long time course of heat hypersensitivity induced by id CFA but, paw edema and mechanical hypersensitivity were independent of Ca_V2.2 channel activity. CFA induced increases in several cytokines in hind paw fluid including IL-6 which was also dependent on Ca_V2.2 channel activity. Using IL-6 specific neutralizing antibodies in vivo we show that IL-6 contributes to heat hypersensitivity and, neutralizing both IL-1α and IL-6 was even more effective at reducing the magnitude and duration of CFA-induced heat hypersensitivity. Our findings demonstrate a functional link between Ca_V2.2 channel activity and the release of IL-6 in skin and show that Ca_V2.2 channels have a privileged role in the induction and maintenance of heat hypersensitivity during chronic forms of neuroinflammation in skin.Significance statement Neuroinflammation can lead to chronic maladaptive pain. Neurotransmitters, ion channels, cytokines, and cytokine receptors are implicated in neuron-immune signaling, but their importance in mediating specific behavioral responses are not fully elucidated. We show that the activity of peripheral Ca_V2.2 calcium ion channels in skin play a unique role in the induction and maintenance of heat hypersensitivity in the CFA model of prolonged neuroinflammation, but they are not involved in the development of edema and mechanical hypersensitivity. Blocking peripheral Ca_V2.2 channel activity reduces local cytokine levels in hind paws injected with CFA including IL-6, and neutralizing IL-6 reduces CFA-induced heat hypersensitivity. Our studies define key signaling molecules that act locally in skin to trigger and maintain heat hypersensitivity during chronic neuroinflammation.

Animals have evolved innate responses to cues including social, food, and predator odors. In the natural environment, animals are faced with choices that involve balancing risk and reward where innate significance may be at odds with internal need. The ability to update the value of a cue through learning is essential for navigating changing and uncertain environments. However, the mechanisms involved in this modulation are not well defined in mammals. We have established a new olfactory assay that challenges a thirsty mouse to choose an aversive odor over an attractive odor in foraging for water, thus overriding their innate behavioral response to odor. Innately, mice prefer the attractive odor port over the aversive odor port. However, decreasing the probability of water at the attractive port leads mice to prefer the aversive port, reflecting a learned override of the innate response to the odors. The orbitofrontal cortex (OFC) is a fourth-order olfactory brain area, involved in flexible value association, with behaviorally relevant outputs throughout the limbic system. We performed optogenetic and chemogenetic silencing experiments that demonstrate the OFC is necessary for this learned modulation of innate aversion to odor. Further, we characterized odor evoked c-fos expression in learned and control mice and found significant suppression of activity in the bed nucleus of the stria terminalis, lateral septum, and central and medial amygdala. These findings reveal that the OFC is necessary for the learned override of innate behavior and may signal to limbic structures to modulate innate response to odor.

In the presence of temporally organized stimuli, there is a tendency to entrain to the beat, even at the neurological level. Previous research has shown that when adults listen to rhythmic stimuli and are asked to imagine the beat, their neural responses are the same as when the beat is physically accented. The current study explores the neural processing of simple beat structures where the beat is physically accented or inferred from a previously presented physically accented beat structure in a passive listening context. We further explore the associations of these neural correlates with behavioral and self-reported measures of musicality. Fifty-seven participants completed a passive listening EEG paradigm, a behavioral rhythm discrimination task, and a self-reported musicality questionnaire. Our findings suggest that when the beat is physically accented, individuals demonstrate distinct neural responses to the beat in the beta (13-23 Hz) and gamma (24-50 Hz) frequency bands. We further find that the neural marker in the beta band is associated with individuals' self-reported musical perceptual abilities. Overall, this study provides insights into the neural correlates of spontaneous beat processing and its connections with musicality.

The Bone Morphogenetic Protein (BMP) signaling pathway is vital in neural progenitor cell proliferation, specification, and differentiation. The BMP signaling antagonist Gremlin 2 (Grem2) is the most potent natural inhibitor of BMP expressed in the adult brain; however its function remains unknown. To address this knowledge gap, we have analyzed mice lacking Grem2 via homologous recombination (Grem2^-/- ). Histological analysis of brain sections revealed significant scattering of CA3 pyramidal cells within the dentate hilus in the hippocampus of Grem2^-/- mice. Furthermore, the number of proliferating neural stem cells and neuroblasts was significantly decreased in the subgranular zone of Grem2^-/- mice compared with that of wild-type (WT) controls. Due to the role of hippocampal neurogenesis in neurological disorders, we tested mice on a battery of neurobehavioral tests. Grem2^-/- mice exhibited increased anxiety on the elevated zero maze in response to acute and chronic stress. Specifically, male Grem2^-/- mice showed increased anxiogenesis following chronic stress, and this was correlated with higher levels of BMP signaling and decreased proliferation in the dentate gyrus. Additionally, when chemically challenged with kainic acid, Grem2^-/- mice displayed a higher susceptibility to and increased severity of seizures compared with WTs. Together, our data indicate that Grem2 regulates BMP signaling and is vital in maintaining homeostasis in adult hippocampal neurogenesis and structure. Furthermore, the lack of Grem2 contributes to the development and progression of neurogenesis-related disorders such as anxiety and epilepsy.

It is a common belief that memories, over time, become progressively independent of the hippocampus and are gradually stored in cortical areas. This view is mainly based on evidence showing that prefrontal cortex (PFC) manipulations impair the retrieval of remote memories, while hippocampal inhibition does not. More controversial is whether activity in the medial PFC is required immediately after learning to initiate consolidation. Another question concerns functional differences among PFC subregions in forming and storing remote memories. To address these issues, we directly contrasted the effects of loss-of-function manipulations of the anterior cingulate cortex (aCC) and the ventromedial PFC, which includes the infralimbic (IL) and prelimbic (PL) cortices, before testing and immediately after training on the ability of CD1 mice to recall the hidden platform location in the Morris water maze. We injected an AAV carrying the hM4Di receptor into the PL-IL or aCC. Interestingly, pretest administrations of clozapine-N-oxide (CNO; 3 mg/kg) revealed that the aCC, but not the PL-IL, was necessary to recall remote spatial information. Furthermore, systemic post-training administration of CNO impaired memory recall at remote, but not recent, time points in both groups. These findings revealed a functional dissociation between the two prefrontal areas, demonstrating that both the PL-IL and the aCC are involved in early consolidation of remote spatial memories, but only the aCC is engaged in their recall.

Two-photon calcium imaging allows for the activity readout of large populations of neurons at single cell resolution in living organisms, yielding new insights into how the brain processes information. Holographic optogenetics allows us to trigger activity of this population directly, raising the possibility of injecting information into a living brain. Optogenetic triggering of activity that mimics "natural" information, however, requires identification of stimulation targets based on real-time analysis of the functional network. We have developed NeuroART (Neuronal Analysis in Real Time), software that provides real-time readout of neuronal activity integrated with downstream analysis of correlations and synchrony and of sensory metadata. On the example of auditory stimuli, we demonstrate real-time inference of the contribution of each neuron in the field of view to sensory information processing. To avoid the limitations of microscope hardware and enable collaboration of multiple research groups, NeuroART taps into microscope data streams without the need for modification of microscope control software and is compatible with a wide range of microscope platforms. NeuroART also integrates the capability to drive a spatial light modulator (SLM) for holographic photostimulation of optimal stimulation targets, enabling real-time modification of functional networks. Neurons used for photostimulation experiments were extracted from Sprague Dawley rat embryos of both sexes.