Browsing by Subject "Interneurons"
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Item Inhibitory Control of Contextual Fear Memory and Memory Specificity(August 2021) Guo, Jun; Pfeiffer, Brad E.; Roberts, Todd; Takahashi, Joseph; Xu, WeiThe brain functions are supported by close interactions between excitation and inhibition. Inhibition contributes to neural computation by gating information flow, tuning the gain of the network, and modulating the output strength of the system. The inhibition in the brain is mainly achieved by GABAergic inhibitory neurons which exert their effect by acting on multiple types of GABA receptors. In this dissertation, I examined the roles of specific types of GABAergic neurons and GABA receptors in learning and memory. The study consists of three major components. In the first component (Chapter 2), I developed a novel technique to selectively target and control GABAergic interneurons (NDNF cells) distributed at the SLM of the hippocampus. With this technique, I found that the activities of NDNF cells increased during memory encoding and decreased during retrieval. Enhancing their activity improved memory encoding but impaired memory retrieval. I further discovered that NDNF cells coordinate memory encoding and retrieval by differentially regulating the two major excitatory inputs to the CA1 region of the hippocampus. In the second component (Chapter 3), I identified a single nucleotide deletion in the gene of a subunit of GABA receptors - Gabra2 that reduces contextual fear memory in C57BL/6J by using quantitative trait locus analysis. In the third component (Chapter 4), I found a change in GABAB receptor-mediated feedforward inhibition led to distinct hippocampal responses to environmental stimuli. This difference further led to distinct hippocampal representation and generalization of contextual fear memory. These studies were carried out at genetic, molecular, circuit, and behavioral levels, and involved a combination of techniques including genetic mapping, in vivo recording, circuit manipulation, and behavior analysis. They exemplify how inhibition shapes neuronal activity and animal behavior. They also provide valuable tools and ideas for future research on the function of inhibition in the brain. The knowledge gained through these studies on how the brain inhibitory network interacts with excitatory neurons to regulate memory facilitates our understanding of the cognitive processes in the brain.Item Investigating Experience-Dependent Plasticity in the Accessory Olfactory Bulb(2018-04-03) Cansler, Hillary Lauren; Roberts, Todd; Meeks, Julian P.; Huber, Kimberly M.; Monteggia, LisaChemosensory information processing in the mouse accessory olfactory system (AOS) guides the expression of social behavior. After salient chemosensory encounters, the accessory olfactory bulb (AOB) experiences changes in the balance of excitation and inhibition at reciprocal synapses between mitral cells (MCs) and local interneurons. The mechanisms underlying these changes remain controversial. Moreover, it remains unclear whether MC-interneuron plasticity is unique to specific behaviors, such as mating, or whether it is a more general feature of the AOB circuit. Here, we describe a population of AOB internal granule cells (IGCs) that upregulate expression of the immediate early gene Arc following the resident-intruder paradigm in an AOS-dependent manner. Targeted electrophysiological studies revealed that Arc-expressing IGCs in acute AOB slices from resident males displayed stronger excitation than non-expressing neighbors when sensory inputs are stimulated. The increased excitability of Arc-expressing IGCs was not correlated with changes in the strength or number of excitatory synapses with MCs, but was instead associated with increased intrinsic excitability and decreased HCN channel-mediated IH currents. Consistent with increased inhibition by IGCs, MCs responded to sensory input stimulation with decreased depolarization and spiking following resident-intruder encounters. Different populations of IGCs are activated following exposure to males and females, suggesting they are activated in an input-specific fashion. We also describe multiple behavioral paradigms that have been designed to assay social recognition following resident-intruder behavior in conjunction with in vivo manipulation of Arc-expressing IGCs. Together, these results reveal that non-mating behaviors drive AOB inhibitory plasticity, and indicate that increased MC inhibition involves intrinsic excitability changes in Arc-expressing interneurons.Item Paradoxically Sparse Chemosensory Tuning in Broadly-Integrating External Granule Cells in the Mouse Accessory Olfactory Bulb(2020-05-01T05:00:00.000Z) Zhang, Xingjian; Pfeiffer, Brad E.; Roberts, Todd; Xu, Wei; Bezprozvanny, Ilya; Meeks, Julian P.Most terrestrial animal species heavily rely on non-volatile chemosignals for conspecific and heterospecific communication. The sensory system responsible for detecting such signals is especially important in guiding animal behavior. Such sensory system in rodents is called accessory olfactory system (AOS). The chemostimulation detection is done by the vomeronasal sensory neurons in the vomeronasal organ (VNO), with their ligand-specific receptors. The electrophysiological signals generated here are then projected to the accessory olfactory bulb (AOB), where the local circuit performs preliminary filtering to the signal. GABAergic interneurons are known to exert their signal sculpturing effect onto principal cells in many brain areas. However, the roles of the AOB GABAergic interneurons are poorly understood. Here, I focus on one genetically defined subtype of GABAergic interneuron, called external granule cell (EGC). Using fast non-ratiometric Ca2+ indicator GCaMP6f specifically expressed in target cell populations on a specialized ex vivo preparation that preserves the functional connections of VNO and AOB, I characterized and compared the tuning properties of EGC and the mitral cells (MC). EGCs show generally narrow tuning preferences towards naturalistic stimulation such as mouse fecal extract and urinal extract, but MCs are much more excitable upon monomolecular sulfated steroid ligands. The result on its appearance contradicts the integrative model as indicated by the circuitry architecture, in which individual EGC broadly connects with MCs by dendrodendritic reciprocal synapses. One explanation is that EGC activation has relatively high threshold. In the presence of sulfated steroids, the excitatory inputs from the activated MCs may not be strong enough to elicit action potentials. Nevertheless, such inputs should be reflected by membrane potential recording of EGCs, in the form of subthreshold depolarizations. To verify this hypothesis, I performed ex vivo electrophysiological recording on EGCs upon the chemostimulation. As expected, subthreshold activities were reliably triggered by sulfated steroid ligands, displaying a 'tuning' profile indistinguishable from that of MCs as indicated by GCaMP6f imaging. AOB granule cells are widely believed to be the information gating module under various behavioral contexts. This unexpected discovery of EGCs might suggest a unique information processing logic of AOS fitting the purpose of rodent social communication.Item Role of Mash1-E Protein Heterodimers in Mash1 Function in the Developing Neural Tube(2003-05-01) Collisson, Tandi Louise; Lu, Q. RichardNeural-specific Class II bHLH transcription factors heterodimerize with ubiquitous Class I bHLH E proteins to form complexes required for neural differentiation. There are four known E proteins, HEB, E12, E47 and E2.2, in the mammalian nervous system, which potentially form heterodimers with Mash1 in the neural tube. To test the relevance of particular Mash1-E protein heterodimer combinations in vivo, I constructed tethered Mash1-E protein heterodimers for over-expression in the chick neural tube. By comparing overexpression of Mash1 with over-expression of these Mash1-E protein heterodimers, their abilities to effect neural differentiation and cell-type specification were analyzed. Mash1-E protein heterodimers are interchangeable in the function of driving neurogenesis in the chick neural tube. The effects of Mash1-E protein heterodimers on cell-type specificity were different, suggesting non-redundant functions in effecting dorsal interneuron populations. Furthermore, additional Mash1 heterodimer partners may be required for the cell-type specification function of Mash1.