The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Utilizing a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice. Surprisingly, NE had little direct effect on modulation of synaptic input at medium spiny neurons (MSNs). In contrast, we report that NE transmission selectively modulates glutamatergic synapses onto PV-expressing fast-spiking interneurons (PV-INs) by recruiting postsynaptically-localized α2 adrenoreceptors (ARs). The synaptic effects of α2-AR activity decrease PV-IN-dependent feedforward inhibition onto medium spiny projection neurons (MSNs) evoked via optogenetic stimulation of cortical afferents to the NAcSh. These findings provide insight into...

Transcranial random noise stimulation (tRNS) over cortical areas has been shown to acutely improve performance in sensory detection tasks. One explanation for this behavioural effect is stochastic resonance, a mechanism that explains how signal processing in non-linear systems can benefit from added noise. While acute noise benefits of electrical random noise stimulation have been demonstrated at the behavioural level as well as in in vitro preparations of neural tissue, it is currently largely unknown whether similar effects can be shown at the neural population level using neurophysiological readouts of human cortex. Here we hypothesized that acute tRNS will increase the responsiveness of primary motor cortex (M1) when probed with transcranial magnetic stimulation. Neural responsiveness was operationalized via the well-known concept of the resting motor threshold (RMT). We showed that tRNS acutely decreases RMT. This effect was small, but it was consistently replicated across four experiments including d...

Alzheimer’s disease (AD) is the most frequent neurodegenerative disorder that commonly causes dementia in the elderly. Recent evidence indicate that network abnormalities, including hypersynchrony, altered oscillatory rhythmic activity, interneuron dysfunction, and synaptic depression may be key mediators of cognitive decline in AD. In this review, we discuss characteristics of neuronal network excitability in AD, and the role of Aβ and Tau in the induction of network hyperexcitability. Many patients harboring genetic mutations that lead to increased Aβ production suffer from seizures and epilepsy prior to the development of plaques. Similarly, pathological accumulation of hyperphosphorylated tau has been associated with hyperexcitability in the hippocampus. We present common and divergent roles of tau and Aβ on neuronal hyperexcitability in AD, and hypotheses that could serve as a template for future experiments. Significance statement Abnormal neuronal network excitability may lead to hypersynchrony, ...

The Stromal interaction molecule 1 (STIM1), is an ER-Ca2+ sensor and an essential component of ER-Ca2+ store operated Ca2+ entry (SOCE). Loss of STIM1 affects metabotropic Glutamate Receptor 1 (mGluR1) mediated synaptic transmission, neuronal Ca2+ homeostasis and intrinsic plasticity in Purkinje Neurons (PNs). Long-term changes of intracellular Ca2+ signaling in PNs lead to neurodegenerative conditions, as evident in individuals with mutations of the ER-Ca2+ channel, the Inositol 1,4,5-triphosphate receptor (IP3R). Here, we asked if changes in such intrinsic neuronal properties, due to loss of STIM1, have an age-dependent impact on PNs. Consequently, we analyzed mRNA expression profiles and cerebellar morphology in PN specific STIM1 knockout mice ( STIM1PKO ) of both sexes across ages. Our study identified a requirement for STIM1 mediated Ca2+ signaling in maintaining the expression of genes belonging to key biological networks of synaptic function and neurite development amongst others. Gene expression ch...

Zebrafish models are used increasingly to study the molecular pathogenesis of Parkinson’s disease (PD), owing to the extensive array of techniques available for their experimental manipulation and analysis. The ascending dopaminergic projection from the posterior tuberculum (diencephalic populations DC2 and DC4) to the subpallium is considered the zebrafish correlate of the mammalian nigrostriatal projection, but little is known about the neurophysiology of zebrafish DC2/4 neurons. This is an important knowledge gap, because autonomous activity in mammalian substantia nigra dopaminergic neurons contributes to their vulnerability in PD models. Using a new transgenic zebrafish line to label living dopaminergic neurons, and a novel brain slice preparation, we carried out whole-cell patch clamp recordings of DC2/4 neurons from adult zebrafish of both sexes. Zebrafish DC2/4 neurons share many physiological properties with mammalian dopaminergic neurons, including the cell-autonomous generation of action potenti...

We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the GPe—they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highlighted the dissociable roles...

There is much debate about the existence and function of neural oscillatory mechanisms in the auditory system. The frequency-following response (FFR) is an index of neural periodicity encoding that can provide a vehicle to study entrainment in frequency ranges relevant to speech and music processing. Criteria for entrainment include the presence of post-stimulus oscillations and phase alignment between stimulus and endogenous activity. To test the hypothesis of entrainment, in experiment 1 we collected FFR data to a repeated syllable using magneto- and electroencephalography in 20 male and female human adults. We observed significant oscillatory activity after stimulus offset in auditory cortex and subcortical auditory nuclei, consistent with entrainment. In these structures the FFR fundamental frequency converged from a lower value over 100 ms to the stimulus frequency, consistent with phase alignment, and diverged to a lower value after offset, consistent with relaxation to a preferred frequency. In expe...

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 (pRF) 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 co...

Human fMRI studies show that insulin influences brain activity in regions that mediate reward and motivation, including the nucleus accumbens (NAc). Insulin receptors are expressed by NAc medium spiny neurons (MSNs), and studies of cultured cortical and hippocampal neurons suggest that insulin influences excitatory transmission via presynaptic and postsynaptic mechanisms. However, nothing is known about how insulin influences excitatory transmission in the NAc. Furthermore, insulin dysregulation accompanying obesity is linked to cognitive decline, depression, anxiety, and altered motivation that rely on NAc excitatory transmission. Using whole-cell patch-clamp and biochemical approaches, we determined how insulin affects NAc glutamatergic transmission in nonobese and obese male rats and the underlying mechanisms. We find that there are concentration-dependent, bidirectional effects of insulin on excitatory transmission, with insulin receptor activation increasing and IGF receptor activation decreasing NAc ...

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 (WES) 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 res...