In the article “The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons,” by Jacob T. Beckley, Sophie Laguesse, Khanhky Phamluong, Nadege Morisot, Scott A. Wegner, and Dorit Ron, which appeared on pages [701–713][1] of the January

Conversion of astroglia into functional neurons has been considered a promising therapeutic strategy for neurodegenerative diseases. Recent studies reported that downregulation of the RNA binding protein, polypyrimidine tract-binding protein 1 (PTBP1), converts astrocytes into neurons in situ in multiple mouse brain regions, consequently improving pathologic phenotypes associated with Parkinson's disease, RGC loss, and aging. Here, we demonstrate that PTBP1 downregulation using an astrocyte-specific AAV-mediated shRNA system fails to convert hippocampal astrocytes into neurons in both male and female wild-type (WT) and β-amyloid (5×FAD) and tau (PS19) Alzheimer's disease (AD) mouse models and fails to reverse synaptic/cognitive deficits and AD-associated pathology in male mice. Similarly, PTBP1 downregulation cannot convert astrocytes into neurons in the striatum and substantia nigra in both male and female WT mice. Together, our study suggests that cell fate conversion strategy for neurodegenerative disea...

The chromatin remodeler CHD8 represents a high-confidence risk factor in autism, a multistage progressive neurological disorder, however the underlying stage-specific functions remain elusive. In this study, by analyzing Chd8 conditional knockout mice (male and female), we find that CHD8 controls cortical neural stem/progenitor cell (NSC) proliferation and survival in a stage-dependent manner. Strikingly, inducible genetic deletion reveals that CHD8 is required for the production and fitness of transit-amplifying intermediate progenitors (IPCs) essential for upper-layer neuron expansion in the embryonic cortex. p53 loss-of-function partially rescue apoptosis and neurogenesis defects in the Chd8 -deficient brain. Further, transcriptomic and epigenomic profiling indicates that CHD8 regulates the chromatin accessibility landscape to activate neurogenesis-promoting factors including TBR2, a key regulator of IPC neurogenesis, while repressing DNA damage- and p53-induced apoptotic programs. In the adult brain, C...

Goal-tracking rats are sensitive to Pavlovian outcome devaluation while sign-tracking rats are devaluation insensitive. During outcome devaluation, goal-tracking (GT) rats flexibly modify responding to cues based on the current value of the associated outcome. However, sign-tracking (ST) rats rigidly respond to cues regardless of the current outcome value. Prior work demonstrated disconnection of the basolateral amygdala (BLA) and anterior insular cortex (aIC) decreased both goal- and sign-tracking behaviors. Given the role of these regions in appetitive motivation and behavioral flexibility we predicted that disrupting BLA to aIC pathway during outcome devaluation would reduce flexibility in GT rats and reduce rigid appetitive motivation in ST rats. We inhibited the BLA to aIC pathway by infusing inhibitory DREADDs (hM4Di-mcherry) or control (mCherry) virus into the BLA and implanted cannulae into the aIC to inhibit BLA terminals using intracranial injections of clozapine N-oxide (CNO). After training, we...

Learning and memory requires coordinated activity between different regions of the brain. Here we studied the interaction between infralimbic medial prefrontal cortex (mPFC) and hippocampal dorsal CA1 during associative odorant discrimination learning in the mouse. We found that as the animal learns to discriminate odorants in a go-no go task, the coupling of high frequency neural oscillations to the phase of theta oscillations (theta-referenced phase-amplitude coupling or tPAC) changes in a manner that results in divergence between rewarded and unrewarded odorant-elicited changes in the theta-phase referenced power (tPRP) for beta and gamma oscillations. In addition, in the proficient animal there was a decrease in the coordinated oscillatory activity between CA1 and mPFC in the presence of the unrewarded odorant. Furthermore, the changes in tPAC resulted in a marked increase in the accuracy for decoding contextual odorant identity from tPRP when the animal became proficient. Finally, we studied the role ...

The molecular circadian clock can be found throughout the body and is essential for the synchronizing cellular physiology with the 24-hour day. However, the role of the clock in regulating the brain’s regenerative potential has not been explored. We report here that murine NG2-glia, the largest population of proliferative cells in the mature central nervous system, rhythmically express circadian clock genes in a 24-hour period, including the critical clock component Bmal1 RNA and BMAL1 protein. Interestingly, daily NG2-glia proliferation preferentially occurs during the time of day in which Bmal1 expression is high, while conditional knockout (CKO) of Bmal1 decreases both cortical NG2-glia density and cellular proliferation. Furthermore, in a neurotrauma model, we show that pathology-induced NG2-glia proliferation is also dependent on Bmal1 expression. Because circadian rhythm disturbances are common in neurologic disorders across the lifespan, including in TBI, these findings bear significant implications...

The outer hair cells in the mammalian cochlea are cellular actuators essential for sensitive hearing. The geometry and stiffness of the structural scaffold surrounding the outer hair cells will determine how the active cells shape mammalian hearing by modulating the organ of Corti (OoC) vibrations. Specifically, the tectorial membrane and the Deiters cell are mechanically in series with the outer hair cell’s hair bundle and soma, respectively. Their mechanical properties and anatomical arrangement must determine the relative motion among different OoC structures. We measured the OoC mechanics in the cochleae acutely excised from young gerbils of both sexes at the resolution fine enough to distinguish the displacement of individual cells. A three-dimensional finite element model of fully deformable OoC was exploited to analyze the measured data in detail. As a means to verify the computer model, the basilar membrane deformations due to static and dynamic stimulations were measured and simulated. Two stiffne...

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 r...

We present a biologically inspired recurrent neural network (RNN) that efficiently detects changes in natural images. The model features sparse, topographic connectivity (st-RNN), closely modeled on the circuit architecture of a “midbrain attention network.” We deployed the st-RNN in a challenging change blindness task, in which changes must be detected in a discontinuous sequence of images. Compared with a conventional RNN, the st-RNN learned 9× faster and achieved state-of-the-art performance with 15× fewer connections. An analysis of low-dimensional dynamics revealed putative circuit mechanisms, including a critical role for a global inhibitory (GI) motif, for successful change detection. The model reproduced key experimental phenomena, including midbrain neurons’ sensitivity to dynamic stimuli, neural signatures of stimulus competition, as well as hallmark behavioral effects of midbrain microstimulation. Finally, the model accurately predicted human gaze fixations in a change blindness experiment, surp...

The identity and location of vocalization pattern generating (VPG) circuits in mammals is debated. Based on physiological experiments investigators suggested anterior brainstem circuits in the reticular formation, and anatomical evidence suggested the nucleus retroambiguus (NRA) in the posterior brainstem, or combinations of these sites as the putative mammalian VPG. Additionally, vocalization loudness is a critical factor in acoustic communication. However, many of the underlying neuronal mechanisms are still unknown. Here we evoked calls by stimulation of the periaqueductal gray (PAG) in anesthetized male rats, performed a large-scale mapping of vocalization-related activity using the activity marker c-fos, and high-density recordings of brainstem circuits using Neuropixels probes. Both c-fos expression and recording of vocalization-related activity point a participation of the NRA in vocalization. More importantly, among our recorded structures, we found that the NRA is the only brainstem area showing a...