Probing the external world is essential for eukaryotes to distinguish beneficial from pathogenic micro-organisms. If it is clear that the main part of this task falls to the immune cells, recent work shows that neurons can also detect microbes, although the molecules and mechanisms involved are less characterized. In Drosophila, detection of bacteria-derived peptidoglycan by pattern recognition receptors of the peptidoglycan recognition protein (PGRP) family expressed in immune cells triggers nuclear factor-κB ( NF -κB)/immune deficiency (IMD)-dependent signaling. We show here that one PGRP protein, called PGRP-LB, is expressed in bitter gustatory neurons of proboscises. In vivo calcium imaging in female flies reveals that the PGRP/IMD pathway is cell-autonomously required in these neurons to transduce the peptidoglycan signal. We finally show that NF-κB/IMD pathway activation in bitter-sensing gustatory neurons influences fly behavior. This demonstrates that a major immune response elicitor and signaling ...

Autism is characterized by two key diagnostic criteria including social deficits and repetitive behaviors. Although recent studies implicated ventral striatum in social deficits and dorsal striatum in repetitive behaviors, here we revealed coexisting and opposite morphologic and functional alterations in the dorsostriatal direct and indirect pathways, and such alterations in these two pathways were found to be responsible, respectively, for the two abovementioned different autism-like behaviors exhibited by male mice prenatally exposed to valproate. The alteration in direct pathway was characterized by a potentiated state of basal activity, with impairment in transient responsiveness of D1-MSNs during social exploration. Concurrent alteration in indirect pathway was a depressed state of basal activity, with enhancement in transient responsiveness of D2-MSNs during repetitive behaviors. A causal relationship linking such differential alterations in these two pathways to the coexistence of these two autism-l...

All pathways targeting the thalamus terminate directly onto the thalamic projection cells. As these cells lack local excitatory interconnections, their computations are fundamentally defined by the type and local convergence patterns of the extrinsic inputs. These two key variables, however, remain poorly defined for the “higher-order relay” (HO) nuclei that constitute most of the thalamus in large-brained mammals, including humans. Here, we systematically analyzed the input landscape of a representative HO nucleus of the mouse thalamus, the posterior nucleus (Po). We examined in adult male and female mice the neuropil distribution of terminals immunopositive for markers of excitatory or inhibitory neurotransmission, mapped input sources across the brain and spinal cord and compared the intranuclear distribution and varicosity size of axons originated from each input source. Our findings reveal a complex landscape of partly overlapping input-specific microdomains. Cortical layer (L)5 afferents from somatos...

Motor adaptation is crucial for performing accurate movements in a changing environment and relies on the cerebellum. Although cerebellar involvement has been well characterized, the neurochemical changes in the cerebellum underpinning human motor adaptation remain unknown. We used a novel magnetic resonance spectroscopic imaging (MRSI) technique to measure changes in the inhibitory neurotransmitter GABA in the human cerebellum during visuomotor adaptation. Participants ( n = 17, six female) used their right hand to adapt to a rotated cursor in the scanner, compared with a control task requiring no adaptation. We spatially resolved adaptation-driven GABA changes at the cerebellar nuclei and cerebellar cortex in the left and the right cerebellar hemisphere independently and found that simple right-hand movements increase GABA in the right cerebellar nuclei and decreases GABA in the left. When isolating adaptation-driven GABA changes, we found that GABA in the left cerebellar nuclei and the right cerebellar ...

The pathophysiological features of ischemia-related blood-brain barrier (BBB) disruption are widely studied using preclinical stroke models. However, in many of these models, craniectomy is required to confirm arterial occlusion via laser Doppler flowmetry or to enable direct ligation of the cerebral artery. In the present study, mice were used to construct a distal middle cerebral artery occlusion (dMCAO) model, a preclinical stroke model that requires craniectomy to enable direct ligation of the cerebral artery, or subjected to craniectomy alone. dMCAO but not craniectomy caused neurodegeneration and cerebral infarction, but both procedures induced an appreciable increase in BBB permeability to Evans blue dye (EBD), fluorescein, and endogenous albumin but not to 10 kD dextran-FITC, leading to cerebral edema. Using rats, we further showed that BBB disruption induced by craniectomy with no evidence of dural tearing was comparable to that induced by craniectomy involving tearing of the dura. In conclusion, ...

Dendritic spines are sub-micron, subcellular compartments whose shape is defined by actin filaments and associated proteins. Accurately mapping the cytoskeleton is a challenge, given the small size of its components. It remains unclear whether the actin-associated structures analyzed in dendritic spines of neurons in vitro apply to dendritic spines of intact, mature neurons in situ. Here, we combined advanced preparative methods with multi-tilt serial section EM tomography and computational analysis to reveal the full three-dimensional internal architecture of spines in the intact brains of male mice at nanometer resolution. We compared hippocampal (CA1) pyramidal cells and cerebellar Purkinje cells in terms of the length-distribution and connectivity of filaments, their branching-angles and absolute orientations, and the elementary loops formed by the network. Despite differences in shape and size across spines and between spine heads and necks, the internal organization was remarkably similar in both neu...

Oral sensory neurons of the geniculate ganglion innervate taste papillae and buds on the tongue and soft palate. Electrophysiological recordings of these neurons and fibers revealed complexity in the number of unique response profiles observed, suggesting there are several distinct neuronal subtypes. Molecular descriptions of these subpopulations are incomplete. We report here the identification of a subpopulation of geniculate ganglion oral sensory neurons in mice by expression of tyrosine hydroxylase (TH). TH-expressing geniculate neurons represent 10-20% of oral sensory neurons and these neurons innervate taste buds in fungiform and anterior foliate taste papillae on the surface of the tongue, as well as taste buds in the soft palate. While 35-50% of taste buds on the tongue are innervated by these TH+ neurons, 100% of soft palate taste buds are innervated. These neurons did not have extragemmal processes outside of taste buds and did not express the mechanosensory neuron-associated gene Ret , suggestin...

At intermediate (‘mesopic’) light levels, rods and cones are both active and can contribute to vision. This presents a challenge to the retina, since the visual responses originating with rods and cones are distinct, yet their visual responses must be seamlessly combined. The current study aimed to establish how the circadian clock regulates rod and/or cone vision in these conditions, given the strong time-of-day change in the reliance on each photoreceptor. Visual responses were recorded in the retina and visual thalamus of anaesthetised male mice at distinct circadian time points, and the method of receptor silent substitution was used to selectively stimulate different photoreceptor types. With stimuli designed to only activate rods, responses in the mesopic range were highly rhythmic, and peaked in amplitude in the subjective night. This rhythm was abolished following intravitreal injection of the gap junction blocker MFA, consistent with a circadian variation in the strength of electrical coupling of ...

Children exposed prenatally to opioids are at an increased risk for behavioral problems and executive function deficits. The prefrontal cortex (PFC) and amygdala (AMG) regulate executive function and social behavior and are sensitive to opioids prenatally. Opioids can bind to toll-like receptor 4 (TLR4) to activate microglia, which may be developmentally important for synaptic pruning. Therefore, we tested the effects of perinatal morphine exposure on executive function and social behavior in male and female mouse offspring, along with microglial and synaptic-related outcomes. Dams were injected once daily s.c. with saline (SAL, n = 8) or morphine (MO, 10 mg/kg, n = 12) throughout pre-gestation, gestation, and lactation until offspring were weaned on postnatal day (P)21. Male MO offspring had impairments in attention and accuracy in the 5-choice serial reaction time task (5CSRTT), while female MO offspring were less affected. Targeted gene expression analysis at P21 in the PFC identified alterations in mic...

GABAA receptors (GABAARs) mediate the majority of fast inhibitory transmission throughout the brain. Although it is widely known that pore-forming subunits critically determine receptor function, it is unclear whether their single-channel properties are modulated by GABAAR-associated transmembrane proteins. We previously identified Shisa7 as a GABAAR auxiliary subunit that modulates the trafficking, pharmacology, and deactivation properties of these receptors. However, whether Shisa7 also regulates GABAAR single-channel properties has yet to be determined. Here, we performed single-channel recordings of α2β3γ2L GABAARs co-transfected with Shisa7 in HEK293T cells and found that while Shisa7 does not change channel slope conductance (iGABA), it reduced the frequency of receptor openings. Importantly, Shisa7 modulates GABAAR gating by decreasing the duration and open probability (Po) within bursts. Through kinetic analysis of individual dwell time components, activation modeling, and macroscopic simulations, ...