The medial nucleus of trapezoid body (MNTB) is a major source of inhibition in auditory brainstem circuitry. The MNTB projects well-timed inhibitory output to principal sound-localization nuclei in the superior olive (SOC) as well as other computationally important centers. Acoustic information is conveyed to MNTB neurons through a single calyx of Held excitatory synapse arising from the cochlear nucleus. The encoding efficacy of this large synapse depends on its activity rate, which is primarily determined by sound intensity and stimulus frequency. However, MNTB activity rate is additionally influenced by inhibition and possibly neuromodulatory inputs, albeit their functional role is unclear. [Happe and Morley (2004)][1] discovered prominent expression of α7 nAChRs in rat SOC, suggesting possible engagement of ACh-mediated modulation of neural activity in the MNTB. However, the existence and nature of this putative modulation have never been physiologically demonstrated. We probed nicotinic cholinergic in...

Events that overlap with previous experience may trigger reactivation of existing memories. However, such reactivation may have different representational consequences within the hippocampal circuit. Computational theories of hippocampal function suggest that dentate gyrus and CA2,3 (DG/CA2,3) are biased to differentiate highly similar memories, whereas CA1 may integrate related events by representing them with overlapping neural codes. Here, we tested whether the formation of differentiated or integrated representations in hippocampal subfields depends on the strength of memory reactivation during learning. Human participants of both sexes learned associations (AB pairs, either face-shape or scene-shape), and then underwent fMRI scanning while they encoded overlapping associations (BC shape-object pairs). Both before and after learning, participants were also scanned while viewing indirectly related elements of the overlapping memories (A and C images) in isolation. We used multivariate pattern analyses t...

In the dorsal horn of the spinal cord, peripheral nerve injury induces structural and neurochemical alterations through which aberrant synaptic signals contribute to the formation of neuropathic pain. However, the role of injured primary afferent terminals in such plastic changes remain unclear. In this study, we investigated the effect of nerve injury on the morphology of cell adhesion molecule L1-CAM (total L1-CAM [tL1-CAM])-positive primary afferent terminals and on the synaptic contact pattern in the dorsal horn. In the confocal images, the tL1-CAM-positive terminals showed morphological changes leading to the formation of hypertrophic varicosities in the c-fiber terminal. These hypertrophic varicosities in the dorsal horn were co-labeled with phosphorylated (Ser1181) L1-CAM (pL1-CAM) and shown to store neurotransmitter peptides, but not when co-labeled with the pre-synaptic marker, synaptophysin. Quantitative analyses based on three-dimensional reconstructed confocal images revealed that peripheral ne...

In the neurobiology of syntax, a methodological challenge is to vary syntax while holding semantics constant. Changes in syntactic structure usually correlate with changes in meaning. We approached this challenge from a new angle. We deployed word lists—typically the unstructured control in studies of syntax—as both test and control stimuli. Three-noun lists ( lamps, dolls, guitars ) were embedded in sentences ( The eccentric man hoarded lamps, dolls, guitars …) and in longer lists ( forks, pen, toilet, rodeo, lamps, dolls, guitars …). This allowed us to minimize contributions from lexical semantics and local phrasal combinatorics: the same words occurred in both conditions and in neither case did the list items locally compose into phrases (e.g. ‘ lamps ’ and ‘ dolls ’ do not form a phrase). Crucially, the list partakes in a syntactic tree in one case but not the other. Lists-in-sentences increased source-localized MEG activity at ∼250-300ms from each of the list item onsets in the left inferior frontal c...

Stress-induced depression is common worldwide. Nucleus accumbens (NAc), a “reward” center, is recently reported to be critical to confer the susceptibility to chronic social defeat stress (CSDS) and the depression-related outcome. However, the underlying molecular mechanisms have not been well characterized. In this study, we induced depression-like behaviors with CSDS and chronic mild stress (CMS) in male mice to mimic social and environmental factors, respectively, and observed animal behaviors with social interaction test, tail suspension test and sucrose preference test. To determine the role of neuronal nitric oxide synthase (nNOS) and its product nitric oxide (NO), we employed brain region-specifically nNOS overexpression and stereotaxic injection of NO inhibitor or donor. Moreover, the downstream molecular cyclin-dependent kinase 5 (CDK5) was explored by conditional knockout and gene mutation. We demonstrate that nNOS-implicated mechanisms in NAc shell (NAcSh), including increased cell number, incre...

Metabotropic glutamate receptor 7 (mGlu7) is an inhibitory heterotrimeric G protein-coupled receptor that modulates neurotransmitter release and synaptic plasticity at presynaptic terminals in the mammalian central nervous system. Recent studies have shown that rare mutations in glutamate receptors and synaptic scaffold proteins are associated with neurodevelopmental disorders (NDDs). However, the role of presynaptic mGlu7 in the pathogenesis of NDDs remains largely unknown. Recent whole-exome sequencing studies in families with NDDs have revealed that several missense mutations (c.1865G>A:p.R622Q; c.461T>C:p.I154T; c.1972C>T:p.R658W and c.2024C>A:p.T675K) or a nonsense mutation (c.1757G>A:p.W586X) in the GRM7 gene may be linked to NDDs. In the present study, we investigated the mechanistic links between GRM7 point mutations and NDD pathology. We find that the pathogenic GRM7 I154T and R658W/T675K mutations lead to the degradation of the mGlu7 protein. In particular, the GRM7 R658W/T675K mutation results i...

Modulators are generally expected to establish a network configuration that is appropriate for the current circumstances. We characterize a situation where the opposite is apparently observed. A network effect of a peptide modulator is counterproductive in that it tends to impede rather than promote the creation of the configuration that is appropriate when the modulator is released. This raises a question, why does release occur? We present data that strongly suggest that it impacts task switching. Our experiments were conducted in an Aplysia feeding network that generates egestive and ingestive motor programs. Initial experiments focused on egestive activity and the neuron B8. As activity becomes egestive there is an increase in synaptic drive to B8 and its firing frequency increases (Wang et al., 2019). We show that as this occurs there is also a persistent current that develops in B8 that is outward rather than inward. Dynamic clamp introduction of this current decreases excitability. When there is an ...

In the neurobiology of syntax, a methodological challenge is to vary syntax while holding semantics constant. Changes in syntactic structure usually correlate with changes in meaning. We approached this challenge from a new angle. We deployed word lists—typically the unstructured control in studies of syntax—as both test and control stimuli. Three-noun lists ( lamps, dolls, guitars ) were embedded in sentences ( The eccentric man hoarded lamps, dolls, guitars …) and in longer lists ( forks, pen, toilet, rodeo, lamps, dolls, guitars …). This allowed us to minimize contributions from lexical semantics and local phrasal combinatorics: the same words occurred in both conditions and in neither case did the list items locally compose into phrases (e.g. ‘ lamps ’ and ‘ dolls ’ do not form a phrase). Crucially, the list partakes in a syntactic tree in one case but not the other. Lists-in-sentences increased source-localized MEG activity at ∼250-300ms from each of the list item onsets in the left inferior frontal c...

The initial encoding of visual information primarily from the contralateral visual field is a fundamental organizing principle of the primate visual system. Recently, the presence of such retinotopic sensitivity has been shown to extend well beyond early visual cortex to regions not historically considered retinotopically sensitive. In particular, human scene-selective regions in parahippocampal and medial parietal cortex exhibit prominent biases for the contralateral visual field. Here we used fMRI to test the hypothesis that the human hippocampus, which is thought to be anatomically connected with these scene-selective regions, would also exhibit a biased representation of contralateral visual space. First, population receptive field mapping with scene stimuli revealed strong biases for the contralateral visual field in bilateral hippocampus. Second, the distribution of retinotopic sensitivity suggested a more prominent representation in anterior medial portions of the hippocampus. Finally, the contralat...

The Golgi cells, together with granule cells and mossy fibers, form a neuronal microcircuit regulating information transfer at the cerebellum input stage. Despite theoretical predictions, little was known about long-term synaptic plasticity at Golgi cell synapses. Here we have used whole-cell patch-clamp recordings and calcium imaging to investigate long-term synaptic plasticity at excitatory synapses impinging on Golgi cells. In acute mouse cerebellar slices, mossy fiber theta-burst stimulation (TBS) could induce either long-term potentiation (LTP) or long-term depression (LTD) at mossy fiber-Golgi cell and granule cell-Golgi cell synapses. This synaptic plasticity showed a peculiar voltage-dependence, with LTD or LTP being favored when TBS induction occurred at depolarized or hyperpolarized potentials, respectively. LTP required, in addition to NMDA channels, activation of T-type Ca2+ channels, while LTD required uniquely activation of L-type Ca2+ channels. Notably, the voltage-dependence of plasticity a...