Negah Rahmati, Kieran P. Normoyle, Joseph Glykys, Volodymyr I. Dzhala, Kyle P. Lillis, et al. (see pages [4957–4975][1]) GABAergic receptors form the cornerstone of inhibitory synaptic signaling in the brain. Classically, ionotropic GABAA receptors pass inward chloride-dominated currents,

An organism’s fitness is determined by how it chooses to adapt to effort in response to challenges. Exertion of effort correlates with activity in dorsomedial prefrontal cortex (dmPFC) and noradrenergic pupil dilation, but little is known about the role of these neurophysiological processes for decisions about future efforts - they may provide anticipatory energization to help us accept the challenge or a cost representation that is weighted against the expected rewards. Here we provide evidence for the former, by measuring pupil and fMRI brain responses while 52 human participants (29 females) chose whether to exert efforts to obtain rewards. Both pupil-dilation rate and dMPFC fMRI activity increased with anticipated effort level, and these increases differ depending on the choice outcome: They were stronger when participants chose to accept the challenge compared to when the challenge was declined. Crucially, the choice-dependent modulation of pupil and brain-activity effort representations were stronger...

Neuropeptide secretion from dense-core vesicles (DCVs) controls many brain functions. Several components of the DCV exocytosis machinery have recently been identified, but the participation of a SEC1/MUNC18 (SM) protein has remained elusive. Here, we tested the ability of the three exocytic SM proteins expressed in the mammalian brain, MUNC18-1/2/3, to support neuropeptide secretion. We quantified DCV exocytosis at a single vesicle resolution upon action potential train-stimulation in mouse CNS neurons (of unknown sex) using pHluorin- and/or mCherry-tagged Neuropeptide-Y (NPY) or Brain-Derived Neurotrophic Factor (BDNF). Conditional inactivation of Munc18-1 abolished all DCV exocytosis. Expression of MUNC18-1, but not MUNC18-2 or MUNC18-3, supported DCV exocytosis in Munc18-1 null neurons. Heterozygous (HZ) inactivation of Munc18-1, as a model for reduced MUNC18-1 expression, impaired DCV exocytosis, especially during the initial phase of train-stimulation, when the release was maximal. These data show tha...

Neuro-immune interaction during development is strongly implicated in the pathogenesis of neurodevelopmental disorders, but the mechanisms that cause neuronal circuit dysregulation are not well understood. We performed in vivo imaging of the developing retinotectal system in the larval zebrafish to characterize the effects of immune system activation on refinement of an archetypal sensory processing circuit. Acute inflammatory insult induced hyper-dynamic remodeling of developing retinal axons in larval fish and increased axon arbor elaboration over days. Using calcium imaging in GCaMP6s transgenic fish we showed that these morphological changes were accompanied by a shift toward decreased visual acuity in tectal cells. This finding was supported by poorer performance in a visually guided behavioral task. We further found that the pro-inflammatory cytokine, interleukin-1β (IL-1β) is upregulated by the inflammatory insult, and that down-regulation of IL-1β abrogated the effects of inflammation on axonal dyn...

Gain-control mechanisms adjust neuronal responses to accommodate the wide range of stimulus conditions in the natural environment. Contrast gain control and extraclassical surround suppression are two manifestations of gain control that govern the responses of neurons in the early visual system. Understanding how these two forms of gain control interact has important implications for the detection and discrimination of stimuli across a range of contrast conditions. Here, we report that stimulus contrast affects spatial integration in the lateral geniculate nucleus of alert macaque monkeys (male and female), whereby neurons exhibit a reduction in the strength of extraclassical surround suppression and an expansion in the preferred stimulus size with low-contrast stimuli compared to high-contrast stimuli. Effects were greater for magnocellular neurons than for parvocellular neurons, indicating stream-specific interactions between stimulus contrast and stimulus size. Within the magnocellular pathway, contrast...

Central pattern generators (CPGs), specialized oscillatory neuronal networks controlling rhythmic motor behaviors such as breathing and locomotion, must adjust their patterns of activity to a variable environment and changing behavioral goals. Neuromodulation adjusts these patterns by orchestrating changes in multiple ionic currents. In the medicinal leech, the endogenous neuromodulator myomodulin speeds up the heartbeat CPG by reducing the electrogenic Na+/K+ pump current and increasing h-current in pairs of mutually inhibitory leech heart interneurons (HNs)which form half-center oscillators (HN HCOs). Here we investigate whether the comodulation of two currents could have advantages over a single current in the control of functional bursting patterns of a CPG. We use a conductance-based biophysical model of an HN HCO to explain the experimental effects of myomodulin. We demonstrate that in the model, comodulation of the Na+/K+ pump current and h-current expands the range of functional bursting activity b...

Learning to recognize and filter familiar, irrelevant sensory stimuli eases the computational burden on the cerebral cortex. Inhibition is a candidate mechanism in this filtration process, and oscillations in the cortical local field potential (LFP) serve as markers of the engagement of different inhibitory neurons. We show here that LFP oscillatory activity in visual cortex is profoundly altered as male and female mice learn to recognize an oriented grating stimulus—low frequency (∼15 Hz peak) power sharply increases while high frequency (∼65 Hz peak) power decreases. These changes report recognition of the familiar pattern, as they disappear when the stimulus is rotated to a novel orientation. Two-photon imaging of neuronal activity reveals that parvalbumin-expressing inhibitory neurons disengage with familiar stimuli and reactivate to novelty, whereas somatostatin-expressing inhibitory neurons show opposing activity patterns. We propose a model in which the balance of two interacting interneuron circuit...

Natural scenes deliver rich sensory information about the world. Decades of research has shown that the scene-selective network in the visual cortex represents various aspects of scenes. However, less is known about how such complex scene information is processed beyond the visual cortex, such as in the prefrontal cortex. It is also unknown how task context impacts the process of scene perception, modulating which scene content is represented in the brain. In this study, we investigate these questions using scene images from four natural scene categories, which also depict two types of scene attributes, temperature (warm or cold), and sound level (noisy or quiet). A group of healthy human subjects from both sexes participated in the present study using fMRI. In the study, participants viewed scene images under two different task conditions; temperature judgment and sound-level judgment. We analyzed how these scene attributes and categories are represented across the brain under these task conditions. Our f...

Maintaining and manipulating sequences online is essential for daily activities such as scheduling a day. In Parkinson’s disease (PD), sequential working memory deficits have been associated with altered regional activation and functional connectivity in the basal ganglia. This study demonstrates that the substantia nigra (SN) integrity correlated with basal ganglia function and sequencing performance in 29 patients with PD (17 women) and 29 healthy controls (HC, 18 women). In neuromelanin-sensitive structural MRI, PD patients showed smaller SN than HC. In a digit ordering task with functional MRI, participants either recalled sequential digits in the original order (‘pure recall’) or rearranged the digits and recalled the new sequence (‘reorder & recall’). PD patients performed less accurately than HC, accompanied by the caudate and pallidal hypo-activation, subthalamic hyper-activation, and weakened functional connectivity between the bilateral SN and all three basal ganglia regions. PD patients with lar...

The sense of balance relies on vestibular hair cells, which detect head motions. Mammals have two types of vestibular hair cell, I and II, with unique morphological, molecular, and physiological properties. Furthermore, each hair cell type synapses on a unique form of afferent nerve terminal. Little is known about the mechanisms in mature animals that maintain the specific features of each hair cell type or its post-synaptic innervation. We found that deletion of the transcription factor Sox2 from type II hair cells in adult mice of both sexes caused many cells in utricles to acquire features unique to type I hair cells and to lose type II-specific features. This cellular transdifferentiation, which included changes in nuclear size, chromatin condensation, soma and stereocilium morphology, and marker expression, resulted in a significantly higher proportion of type I-like hair cells in all epithelial zones. Furthermore, Sox2 deletion from type II hair cells triggered non-cell autonomous changes in vestibul...