Circadian rhythms have been extensively studied in Drosophila ; however, still little is known about how the electrical properties of clock neurons are specified. We have performed a behavioral genetic screen through the downregulation of candidate ion channels in the lateral ventral neurons (LNvs) and show that the hyperpolarization-activated cation current Ih is important for the behaviors that the LNvs influence: temporal organization of locomotor activity, analyzed in males, and sleep, analyzed in females. Using whole-cell patch clamp electrophysiology we demonstrate that small LNvs (sLNvs) are bursting neurons, and that Ih is necessary to achieve the high-frequency bursting firing pattern characteristic of both types of LNvs in females. Since firing in bursts has been associated to neuropeptide release, we hypothesized that Ih would be important for LNvs communication. Indeed, herein we demonstrate that Ih is fundamental for the recruitment of pigment dispersing factor (PDF) filled dense core vesicles...

Age-related memory deficits are correlated with neural hyperactivity in the CA3 region of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from young and aged, male, Long–Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite, decreasing trend, in that CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared with young (Y) rats. We sugg...

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...

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 ...