Autism spectrum disorder (ASD) is a common neurodevelopmental condition for which there are no pharmacological therapies that effectively target its core symptomatology. Animal models of syndromic forms of ASD, such as neurofibromatosis type 1, may be of use in screening for such treatments. Drosophila larvae lacking Nf1 expression exhibit tactile hypersensitivity following mechanical stimulation, proposed to mirror the sensory sensitivity issues comprising part of the ASD diagnostic criteria. Such behavior is associated with synaptic dysfunction at the neuromuscular junction (NMJ). Both phenotypes may thus provide tractable outputs with which to screen for potential ASD therapies. In this study, we demonstrate that, while loss of Nf1 expression within the embryo is sufficient to impair NMJ synaptic transmission in the larva, constitutive Nf1 knock-down is required to induce tactile hypersensitivity, suggesting that a compound must be administered throughout development to rescue this behavior. With such a...

Exercise may prevent or delay aging-related memory loss and neurodegeneration. In rodents, running increases the number of adult-born neurons in the dentate gyrus (DG) of the hippocampus, in association with improved synaptic plasticity and memory function. However, it is unclear whether adult-born neurons remain fully integrated into the hippocampal network during aging and whether long-term running affects their connectivity. To address this issue, we labeled proliferating DG neural progenitor cells with retrovirus expressing the avian TVA receptor in two-month-old sedentary and running male C57Bl/6 mice. More than six months later, we injected EnvA-pseudotyped rabies virus into the DG as a monosynaptic retrograde tracer, to selectively infect TVA expressing “old” new neurons. We identified and quantified the direct afferent inputs to these adult-born neurons within the hippocampus and (sub)cortical areas. Here, we show that long-term running substantially modifies the network of the neurons generated in...

The parabrachial complex (PB) is critically involved in aversive processes, and chronic pain is associated with amplified activity of PB neurons in rodent models of neuropathic pain. Here, we demonstrate that catecholaminergic input from the caudal nucleus of the solitary tract (cNTScat), a stress responsive region that integrates interoceptive and exteroceptive signals, causes amplification of PB activity and their sensory afferents. We used a virally mediated expression of a norepinephrine (NE) sensor, NE2h, fiber photometry, and extracellular recordings in anesthetized mice to show that noxious mechanical and thermal stimuli activate cNTS neurons. These stimuli also produce prolonged NE transients in PB that far outlast the noxious stimuli. Similar NE transients can be evoked by focal electrical stimulation of cNTS, a region that contains the noradrenergic A2 cell group that projects densely on PB. In vitro , optical stimulation of cNTScat terminals depolarized PB neurons and caused a prolonged increase...

It is well-known that both hand movements and mental representations of movement lead to event-related desynchronization (ERD) of the electroencephalogram (EEG) recorded over the corresponding cortical motor areas. However, the relationship between ERD in somatosensory cortical areas and mental representations of tactile sensations is not well-understood. In this study, we employed EEG recordings in healthy humans to compare the effects of real and imagined vibrotactile stimulation of the right hand. Both real and imagined sensations produced contralateral ERD patterns, particularly in the μ-band and most significantly in the C3 region. Building on these results and the previous literature, we discuss the role of tactile imagery as part of the complex body image and the potential for using EEG patterns induced by tactile imagery as control signals in brain-computer interfaces (BCIs). Combining this approach with motor imagery could improve the performance of BCIs intended for rehabilitation of sensorimotor...

Transcranial random noise stimulation (tRNS) has been shown to significantly improve visual perception. Previous studies demonstrated that tRNS delivered over cortical areas acutely enhances visual contrast detection of weak stimuli. However, it is currently unknown whether tRNS-induced signal enhancement could be achieved within different neural substrates along the retino-cortical pathway. In 3 experimental sessions, we tested whether tRNS applied to the primary visual cortex(V1) and/or to the retina improves visual contrast detection. We first measured visual contrast detection threshold (VCT; N=24, 16females) during tRNS delivery separately over V1 and over the retina, determined the optimal tRNS intensities for each individual(ind-tRNS), and retested the effects of ind-tRNS within the sessions. We further investigated whether we could reproduce the ind-tRNS-induced modulation on a different session (N=19, 14females). Finally, we tested whether the simultaneous application of ind-tRNS to the retina an...

While animal and human decision strategies are typically explained by model-free and model-based reinforcement learning, their choice sequences often follow simple procedures based on working memory of past actions and rewards. Here we address how working memory-based choice strategies, such as win-stay-lose-switch (WSLS), are represented in the prefrontal and motor cortico-basal ganglia loops by simultaneous recording of neuronal activities in the dorsomedial striatum (DMS), the dorsolateral striatum (DLS), the medial prefrontal cortex (mPFC), and the primary motor cortex (M1). In order to compare neuronal representations when rats employ working memory-based strategies, we developed a new task paradigm, a continuous/intermittent choice task, consisting of choice and no-choice trials. While the continuous condition (CC) consisted of only choice trials, in the intermittent condition (IC), a no-choice trial was inserted after each choice trial to disrupt working memory of the previous choice and reward. Beh...

Mesolimbic nicotinic acetylcholine receptor (nAChRs) activation is necessary for nicotine reinforcement behavior, but it is unknown whether selective activation of nAChRs in the dopamine (DA) reward pathway is sufficient to support nicotine reinforcement. In this study, we tested the hypothesis that activation of β2-containing (β2*) nAChRs on VTA neurons is sufficient for intravenous nicotine self-administration (SA). We expressed β2 nAChR subunits with enhanced sensitivity to nicotine (referred to as β2Leu9′Ser) in the VTA of male Sprague Dawley (SD) rats, enabling very low concentrations of nicotine to selectively activate β2* nAChRs on transduced neurons. Rats expressing β2Leu9′Ser subunits acquired nicotine SA at 1.5 μg/kg/infusion, a dose too low to support acquisition in control rats. Saline substitution extinguished responding for 1.5 μg/kg/inf, verifying that this dose was reinforcing. β2Leu9′Ser nAChRs also supported acquisition at the typical training dose in rats (30 μg/kg/inf) and reducing the ...

Therapeutic hypothermia is well established as a standard treatment for infants with hypoxic-ischemic (HI) encephalopathy but it is only partially effective. The potential for combination treatments to augment hypothermic neuroprotection has major relevance. Our aim was to assess the effects of treating newborn rats following HI injury with cannabidiol (CBD) at 0.1 or 1 mg/kg, i.p., in normothermic (37.5°C) and hypothermic (32.0°C) conditions, from 7 d of age (neonatal phase) to 37 d of age (juvenile phase). Placebo or CBD was administered at 0.5, 24, and 48 h after HI injury. Two sensorimotor (rotarod and cylinder rearing) and two cognitive (novel object recognition and T-maze) tests were conducted 30 d after HI. The extent of brain damage was determined by magnetic resonance imaging, histologic evaluation, magnetic resonance spectroscopy, amplitude-integrated electroencephalography, and Western blotting. At 37 d, the HI insult produced impairments in all neurobehavioral scores (cognitive and sensorimotor...

Reverberation is ubiquitous in everyday acoustic environments. It degrades both binaural cues and the envelope modulations of sounds and thus can impair speech perception. Still, both humans and animals can accurately perceive reverberant stimuli in most everyday settings. Previous neurophysiological and perceptual studies have suggested the existence of neural mechanisms that partially compensate for the effects of reverberation. However, these studies were limited by their use of either highly simplified stimuli or rudimentary reverberation simulations. To further characterize how reverberant stimuli are processed by the auditory system, we recorded single-unit (SU) and multiunit (MU) activity from the inferior colliculus (IC) of unanesthetized rabbits in response to natural speech utterances presented with no reverberation (“dry”) and in various degrees of simulated reverberation (direct-to-reverberant energy ratios (DRRs) ranging from 9.4 to –8.2 dB). Linear stimulus reconstruction techniques ([Mesgara...

The accumulation of α-synuclein (α-syn)-enriched protein aggregates is thought to arise from dysfunction in degradation systems within the brain. Recently, missense mutations of SYNJ1 encoding the SAC1 and 5’-phosphatase domains have been found in families with hereditary early-onset Parkinsonism. Previous studies showed that Synj1 haploinsufficiency ( Synj1 +/−) leads to accumulation of the autophagy substrate p62 and pathologic α-syn proteins in the midbrain (MB) and striatum of aged mice. In this study, we aim to investigate the neuronal degradation pathway using the Synj1 +/− MB culture from mouse pups of mixed sex as a model. Our data show that GFP-LC3 puncta formation and cumulative mKeima puncta formation are unaltered at baseline in Synj1 +/− MB neurons. However, GFP-LAMP1 puncta is reduced with a similar decrease in endogenous proteins, including lysosomal-associated membrane protein (LAMP)1, LAMP2, and LAMP2A. The LAMP1 vesicles are hyperacidified with enhanced enzymatic activity in Synj1 +/− MB ...