Visuospatial attention is a prerequisite for the performance of visually guided movements: Perceptual discrimination is regularly enhanced at target locations prior to movement initiation. It is known that this attentional prioritization evolves over the time of movement preparation; however, it is not clear whether this build-up simply reflects a time requirement of attention formation or whether, instead, attention build-up reflects the emergence of the movement decision. To address this question, we combined behavioral experiments, psychophysics, and computational decision-making models to characterize the time course of attention build-up during motor preparation. Participants (n = 46, 29 female) executed center-out reaches to one of two potential target locations and reported the identity of a visual discrimination target that occurred concurrently at one of various time-points during movement preparation and execution. Visual discrimination increased simultaneously at the two potential target locatio...

Nucleus basalis magnocellularis (NBM) cholinergic projections to the basolateral amygdala (BLA) regulate the acquisition and consolidation of fear- and anxiety-like behaviors. However, it is unclear whether the alterations in the NBM-BLA circuit promote negative affect during ethanol withdrawal. Therefore, we performed ex vivo whole-cell patch clamp electrophysiology in both the NBM and the BLA of male Sprague-Dawley rats following 10 days of chronic intermittent ethanol (CIE) exposure and 24 hours of withdrawal (WD). We found that CIE exposure and withdrawal enhanced the neuronal excitability of NBM putative ‘cholinergic’ neurons. We subsequently used optogenetics to directly manipulate NBM terminal activity within the BLA and measure cholinergic modulation of glutamatergic afferents and BLA pyramidal neurons. Our findings indicate that CIE and withdrawal upregulate NBM cholinergic facilitation of glutamate release via activation of presynaptic nicotinic acetylcholine receptors. Ethanol withdrawal-induced...

Historically, diabetic retinopathy has been recognized as a vascular disease. Recent clinical evidence suggests the initiation of diabetic retinopathy with neuropathy rather than microangiopathy. However, the molecular mechanism that drives diabetic retinopathy-associated neuropathy remains mostly unexplored. Here, we reported progressive diabetic retinopathy defects in blood glucose levels, shortening of cone segments and uncoupled appearance of retinal vascular abnormalities from pdx1 +/− mutants zebrafish to glucose-treated pdx1 +/− mutants zebrafish of both sexes. Further single-cell transcriptomic analysis revealed cones as the most vulnerable retinal neuron type that underwent three developmentally progressive cell states (States 1-3), predominantly present in WT animals, pdx1 +/− mutants , and glucose-treated pdx1 +/− mutants , respectively. Mechanistically, the expression of hcn1 was progressively decreased in cones during its transition from State 1 to State 3. Furthermore, genetic hcn1 disruption...

The human visual system consists of multiple topographic maps that extend from the early visual cortex (EVC) along the dorsal and ventral processing streams. Responses to illusory shapes within these maps have been demonstrated in the ventral stream areas, in particular the lateral occipital complex (LOC). Recently, the intraparietal sulcus (IPS) of the dorsal stream has been linked to the processing of illusory shapes defined by motion. It remains unclear whether the topographically organized parietal areas also respond to stationary illusory shapes, which would suggest their generic role in representing illusory content. In the current study we measured brain responses using fMRI while 30 human participants (12 male) observed flickering inducers around the fixation task. The inducers either formed an illusory diamond in the center, a triangle in the left or right hemifield, or were inverted such that no illusory figure was formed. We compared responses of parietal regions IPS0-IPS5 and SPL1 to each illus...

Chronic visceral pain is a major challenge for both patients and health providers. Although the central sensitization of the brain is thought to play an important role in the development of visceral pain, the detailed neural circuits remain largely unknown. Using a well-established chronic visceral hypersensitivity model induced by neonatal maternal deprivation (NMD) in male mice, we identified a distinct pathway whereby the claustrum (CL) glutamatergic neuron projecting to the anterior cingulate cortex (ACC) is critical for visceral pain but not for CFA-evoked inflammatory pain. By a combination of in vivo circuit-dissecting extracellular electrophysiological approaches and visceral pain related electromyographic (EMG) recordings, we demonstrated that optogenetic inhibition of CL glutamatergic activity suppressed the ACC neural activity and visceral hypersensitivity of NMD mice whereas selective activation of CL glutamatergic activity enhanced the ACC neural activity and evoked visceral pain of control mi...

Aquaporin-4 (AQP4) is characterized by the formation of orthogonal arrays of particles (OAPs) comprising its M1 and M23 isoforms in the plasma membrane. However, the biological importance of OAP formation is obscure. Here, we developed an OAP depolymerization male mouse model by transgenic knock-in of an AQP4-A25Q mutation. Analyses of the mutant brain tissue using blue native polyacrylamide gel electrophoresis, super-resolution imaging, and immunogold electron microscopy revealed remarkably reduced OAP structures and glial endfeet localization of the AQP4-A25Q mutant protein without effects on its overall mRNA and protein expression. AQP4A25Q/A25Q mice showed better survival and neurologic deficit scores when cerebral edema was induced by water intoxication or middle cerebral artery occlusion/reperfusion. The brain water content and swelling of pericapillary astrocytic endfeet processes in AQP4A25Q/A25Q mice were significantly reduced, functionally supporting decreased AQP4 protein expression at the blood...

During recovery from anesthesia, brain activity switches abruptly between a small set of discrete states. Surprisingly, this switching also occurs under constant doses of anesthesia, even in the absence of stimuli. These metastable states and the transitions between them are thought to form a “scaffold” that ultimately guides the brain back to wakefulness. The processes that constrain cortical activity patterns to these states and govern how states are coordinated between different cortical regions are unknown. If state transitions were driven by subcortical modulation, different cortical sites should exhibit near-synchronous state transitions. Conversely, spatiotemporal heterogeneity would suggest that state transitions are coordinated through corticocortical interactions. To differentiate between these hypotheses, we quantified synchrony of brain states in male rats exposed to a fixed isoflurane concentration. States were defined from spectra of local field potentials recorded across layers of visual and...

Kainate receptors (KARs) form a family of ionotropic glutamate receptors which regulate the activity of neuronal networks by both pre- and post-synaptic mechanisms. Their implication in pathologies is well documented for epilepsy. The higher prevalence of epileptic symptoms in Alzheimer disease (AD) patients questions the role of KARs in AD. Here we investigated whether the synaptic expression and function of KARs was impaired in mouse models of AD. We addressed this question by immunostaining and electrophysiology at synapses between mossy fibers and CA3 pyramidal cells, in which KARs are abundant and play a prominent physiological role. We observed a decrease of the immunostaining for GluK2 in the stratum lucidum in CA3, and of the amplitude and decay time of synaptic currents mediated by GluK2-containing KARs in an amyloid mouse model (male and female APP/PS1 mice) of AD. Interestingly, a similar phenotype was observed in CA3 pyramidal cells in male and female mice with a genetic deletion of either pres...

The mediodorsal thalamus is a multimodal region involved in a variety of cognitive behaviors, including olfactory attention, odor discrimination, and the hedonic perception of flavors. Although the mediodorsal thalamus forms connections with principal regions of the olfactory and gustatory networks, its role in processing olfactory and gustatory signals originating from the mouth remains unclear. Here, we recorded single-unit activity in the mediodorsal thalamus of behaving female rats during the intraoral delivery of individual odors, individual tastes, and odor-taste mixtures. Our results are the first to demonstrate that neurons in the mediodorsal thalamus dynamically encode chemosensory signals originating from the mouth. This chemoselective population is broadly tuned, exhibits excited and suppressed responses, and responds to odor-taste mixtures differently than an odor or taste alone. Furthermore, a subset of chemoselective neurons encodes the palatability-related features of tastes and may represen...