Habituated animals retain a latent capacity for robust engagement with familiar stimuli. In most instances, the ability to override habituation is best explained by postulating that habituation arises from the potentiation of inhibitory inputs onto stimulus-encoding assemblies and that habituation override occurs through disinhibition. Previous work has shown that inhibitory plasticity contributes to specific forms of olfactory and gustatory habituation in Drosophila . Here, we analyze how exposure to a novel stimulus causes override of gustatory (proboscis extension reflex; PER) habituation. While brief sucrose contact with tarsal hairs causes naive Drosophila to extend their proboscis, persistent exposure reduces PER to subsequent sucrose stimuli. We show that in so habituated animals, either brief exposure of the proboscis to yeast or direct thermogenetic activation of sensory neurons restores PER response to tarsal sucrose stimulation. Similar override of PER habituation can also be induced by brief th...

Working memory ability continues to mature into adulthood in humans and nonhuman primates. At the single-neuron level, adolescent development is characterized by increased prefrontal firing rate in the delay period, but less is known about how coordinated activity between neurons is altered. Local field potentials (LFPs) provide a window into the computations conducted by the local network. To address the effects of adolescent development on LFP activity, three male rhesus monkeys were trained to perform an oculomotor delayed response task and tested at both the adolescent and adult stages. Simultaneous single-unit and LFP signals were recorded from areas 8a and 46 of the dorsolateral prefrontal cortex. In both the cue and delay period, power relative to baseline in the gamma frequency range (32–128 Hz) was higher in the adolescent than the adult stage. The changes between developmental stages could not be accounted for by differences in performance and were observed in more posterior as well as more anter...

Bayesian inference provides an elegant theoretical framework for understanding the characteristic biases and discrimination thresholds in visual speed perception. However, the framework is difficult to validate because of its flexibility and the fact that suitable constraints on the structure of the sensory uncertainty have been missing. Here, we demonstrate that a Bayesian observer model constrained by efficient coding not only well explains human visual speed perception but also provides an accurate quantitative account of the tuning characteristics of neurons known for representing visual speed. Specifically, we found that the population coding accuracy for visual speed in area MT (“neural prior”) is precisely predicted by the power-law, slow-speed prior extracted from fitting the Bayesian observer model to psychophysical data (“behavioral prior”) to the point that the two priors are indistinguishable in a cross-validation model comparison. Our results demonstrate a quantitative validation of the Bayesi...

Since the discovery that the mammalian nervous system holds regenerative capacity ([Cruikshank, 1795][1]), researchers have not ceased to investigate how to enhance neuroregeneration after injury and disease. Despite centuries of effort, however, regeneration in the CNS is still greatly limited, and

PEGPH20, a human recombinant hyaluronidase, has been proposed as a coadjutant to pancreatic cancer chemotherapy. In early trials, patients reported increased widespread muscle pain as the main adverse reaction to PEGPH20. To understand how PEGPH20 caused musculoskeletal pain, we systemically administered PEGPH20 to male mice and measured voluntary wheel activity and pain-related behaviors. These were paired with ex-vivo electrophysiology of primary sensory neurons, whole DRG realtime PCR, and immunohistochemistry of hindpaw muscle. PEGPH20 induced significantly lower wheel running, compared to vehicle treated animals, and decreased mechanical withdrawal thresholds 5 days after PEGPH20 injections. Chemo-sensory muscle afferents showed increased responses to noxious chemical stimulation of their receptive fields in the PEGPH20 treated group. This was correlated with upregulation of the NGF receptor TrkA, the transient receptor potential vanilloid type 1 (TRPV1) channel and ATP-sensitive channel P2X3 in the D...

Calcium is an important second messenger regulating a bioenergetic response to the workloads triggered by neuronal activation. In embryonic mouse cortical neurons using glucose as only fuel, activation by NMDA elicits a strong workload (ATP demand) dependent on Na+ and Ca2+ entry, and stimulates glucose uptake, glycolysis, pyruvate and lactate production and OXPHOS in a Ca2+-dependent way. We find that Ca2+-upregulation of glycolysis, pyruvate levels and respiration, but not glucose uptake, all depend on Aralar/AGC1/Slc25a12, the mitochondrial aspartate-glutamate carrier, component of the malate-aspartate shuttle (MAS). MAS activation increases glycolysis, pyruvate production and respiration, a process inhibited in the presence of BAPTA-AM suggesting that the Ca2+ binding motifs in Aralar may be involved in the activation. MCU silencing had no effect indicating that none of these processes required MCU-dependent mitochondrial Ca2+ uptake. The neuronal respiratory response to carbachol was also dependent on...

Oxytocin receptors (OTR) have been found in the paraventricular thalamus (PVT) for the regulation of feeding and maternal behaviors. However, the functional projections of OTR-expressing PVT neurons remain largely unknown. Here, we used chemogenetic and optogenetic tools to test the role of OTR-expressing PVT neurons and their projections in the regulation of food intake in both male and female OTR-Cre mice. We found chemogenetic activation of OTR-expressing PVT neurons promoted food-seeking under trials with a progressive ratio (PR) schedule of reinforcement. Using Feeding Experimentation Devices (FED) for real-time meal measurements, we found chemogenetic activation of OTR-expressing PVT neurons increased meal frequency but not cumulative food intake due to a compensatory decrease in meal sizes. In combination with anterograde neural tracing and slice patch-clamp recordings, we found optogenetic stimulation of PVT OTR terminals excited neurons in the posterior basolateral amygdala (pBLA) and nucleus accu...

Anticipatory covert spatial attention improves performance on tests of visual detection and discrimination, and shifts are accompanied by decreases and increases of alpha-band power at EEG electrodes corresponding to the attended and unattended location, respectively. Although the increase at the unattended location is often interpreted as an active mechanism (e.g., inhibiting processing at the unattended location), most experiments can’t rule out the alternative possibility that it is a secondary consequence of selection elsewhere. To adjudicate between these accounts, we designed a Posner-style visual cueing task in which male and female human participants made orientation judgments of targets appearing at one of four locations: up , down , right , or left . Critically, trials were blocked such that within a block the locations along one meridian alternated in status between attended and unattended , and targets never appeared at the other two, making them irrelevant . Analyses of the concurrently measur...

Dysregulation of autophagic pathways leads to accumulation of abnormal proteins and damaged organelles in many neurodegenerative disorders, including Parkinson's disease (PD) and Lewy body dementia (LBD). Autophagy-related dysfunction may also trigger secretion and spread of misfolded proteins, such as α-synuclein (α-syn), the major misfolded protein found in PD/LBD. However, the mechanism underlying these phenomena remains largely unknown. Here, we used cell-based models, including human induced pluripotent stem cell-derived neurons, CRISPR/Cas9 technology, and male transgenic PD/LBD mice, plus vetting in human postmortem brains (both male and female). We provide mechanistic insight into this pathologic pathway. We find that aberrant S-nitrosylation of the autophagic adaptor protein p62 causes inhibition of autophagic flux and intracellular buildup of misfolded proteins, with consequent secretion resulting in cell-to-cell spread. Thus, our data show that pathologic protein S-nitrosylation of p62 represent...

Hilar mossy cells regulate network function in the hippocampus through both direct excitation and di-synaptic inhibition of dentate granule cells (DGCs). Substantial mossy cell loss accompanies hippocampal circuit changes in epilepsy. We examined the contribution of surviving mossy cells to network activity in the reorganized dentate gyrus after pilocarpine-induced status epilepticus (SE). To examine functional circuit changes, we optogenetically stimulated mossy cells in acute hippocampal slices from male mice. In control mice, activation of mossy cells produced monosynaptic excitatory and di-synaptic GABAergic currents in DGCs. In pilocarpine-treated mice, mossy cell density and excitation of DGCs were reduced in parallel, with only a minimal reduction in feedforward inhibition, enhancing the inhibition/excitation ratio. Surprisingly, mossy cell-driven excitation of parvalbumin-positive (PV+) basket cells, primary mediators of feed-forward inhibition, was maintained. Our results suggest that mossy cell o...