The hypokinetic motor symptoms of Parkinson's disease (PD) are closely linked with a decreased motor cortical output as a consequence of elevated basal ganglia inhibition. However, whether and how the loss of dopamine (DA) alters the cellular properties of motor cortical neurons in PD remains undefined. We induced parkinsonism in adult C57BL/6 mice of both sexes by injecting neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle. By using ex vivo patch-clamp recording and retrograde tracing approach, we found that the intrinsic excitability of pyramidal tract neurons (PTNs) in the primary motor cortical (M1) layer (L)5b was greatly decreased in parkinsonism; but the intratelencephalic neurons (ITNs) were not affected. The cell type-specific intrinsic adaptations were associated with a depolarized threshold and broadened width of action potentials (APs) in PTNs. Moreover, the loss of midbrain dopaminergic neurons impaired the capability of M1 PTNs to sustain high-frequency firing, which co...

People with strabismus acquired during childhood do not experience diplopia (double vision). To investigate how perception of the duplicate image is suppressed, we raised two male monkeys with alternating exotropia by disinserting the medial rectus muscle in each eye at age four weeks. Once the animals were mature, they were brought to the laboratory and trained to fixate a small spot while recordings were made in primary visual cortex (V1). Drifting gratings were presented to the receptive fields of 500 single neurons for eight interleaved conditions: (1) right eye monocular; (2) left eye monocular; (3) right eye's field, right eye fixating; (4) right eye's field, left eye fixating; (5) left eye's field, right eye fixating; (6) left eye's field, left eye fixating; (7) both eyes' fields, right eye fixating; (8) both eyes' fields, left eye fixating. As expected, ocular dominance histograms showed a monocular bias compared with normal animals, but many cells could still be driven via both eyes. Overall, neur...

In 1981, I published a paper in the first issue of The Journal of Neuroscience with my postdoctoral mentor, Richard Bunge. At that time, the long-standing belief that each neuron expressed only one neurotransmitter, known as Dale's Principle ([Dale, 1935][1]), was being hotly debated following a report by French embryologist Nicole Le Douarin showing that neural crest cells destined for one transmitter phenotype could express characteristics of another if transplanted to alternate sites in the developing embryo ([Le Douarin, 1980][2]). In the Bunge laboratory, we were able to more directly test the question of phenotypic plasticity in the controlled environment of the tissue culture dish. Thus, in our paper, we grew autonomic catecholaminergic neurons in culture under conditions which promoted the acquisition of cholinergic traits and showed that cells did not abandon their inherited phenotype to adopt a new one but instead were capable of dual transmitter expression. In this Progressions article, I detail...

Dopaminergic neurons of the substantia nigra pars compacta (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. Here, we used live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. Specifically, the frequency of hub-like neurons was significantly lower in SNC than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. We tested this hypothesis, in DAT-cre/loxP-GCaMP6f mice of either sex, when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC or VTA networks. Neur...

The dorsomedial prefrontal cortex (dmPFC) has been linked to avoidance and decision-making under conflict, key neural computations altered in anxiety disorders. However, the heterogeneity of prefrontal projections has obscured identification of specific top-down projections involved. While the dmPFC–amygdala circuit has long been implicated in controlling reflexive fear responses, recent work suggests that dmPFC–dorsomedial striatum (DMS) projections may be more important for regulating avoidance. Using fiber photometry recordings in both male and female mice during the elevated zero maze task, we show heightened neural activity in frontostriatal but not frontoamygdalar projection neurons during exploration of the anxiogenic open arms. Additionally, using optogenetics, we demonstrate that this frontostriatal projection preferentially excites postsynaptic D1 receptor-expressing neurons in the DMS and causally controls innate avoidance behavior. These results support a model for prefrontal control of defensi...

Behavioral flexibility, the ability to adapt behaviors in response to changes in the environment, is of great importance for everyday functioning ([Klanker et al., 2013][1]). Behavioral flexibility is typically assessed using reversal learning tasks, in which subjects learn to perform a specific

Clinical reports suggest that the coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome (SARS)-coronavirus-2 (CoV-2) has not only taken millions of lives, but has also created a major crisis of neurologic complications that persist even after recovery from the disease. Autopsies of patients confirm the presence of the coronaviruses in the CNS, especially in the brain. The invasion and transmission of SARS-CoV-2 in the CNS is not clearly defined, but, because the endocytic pathway has become an important target for the development of therapeutic strategies for COVID-19, it is necessary to understand endocytic processes in the CNS. In addition, mitochondria and mechanistic target of rapamycin (mTOR) signaling pathways play a critical role in the antiviral immune response, and may also be critical for endocytic activity. Furthermore, dysfunctions of mitochondria and mTOR signaling pathways have been associated with some high-risk conditions such as diabetes and immunodeficienc...

Congenital sensorineural hearing loss (SNHL) affects thousands of infants each year and results in significant delays in speech and language development. Previous studies have shown that early exposure to a simple augmented acoustic environment (AAE) can limit the effects of progressive SNHL on hearing sensitivity. However, SNHL is also accompanied by hearing loss that is not assessed on standard audiological exams, such as reduced temporal processing acuity. To assess whether sound therapy may improve these deficits, a mouse model of congenital SNHL was exposed to simple or temporally complex AAE. The DBA/2J mouse strain develops rapid, base to apex, progressive sensorineural hearing loss (SNHL) beginning at birth and is functionally deaf by 6 months of age. Hearing sensitivity and auditory brainstem function was measured using otoacoustic emissions, auditory brainstem response and extracellular recording from the inferior colliculus in mice following exposure to 60 days of continuous AAE and in unexposed...

Sleep spindles, bursts of electroencephalogram (EEG) activity in the sigma-frequency (11-16 Hz) range, may be biomarkers of cortical development. Studies capturing the transition to adolescence are needed to delineate age-, sex- and pubertal-related changes in sleep spindles at the population-level. We analyzed the sleep EEG of 572 subjects 6-21y (48% female) and 332 subjects 5-12y (46% female) followed-up at 12-22y. From 6y to 21y, spindle density (p-quadratic=0.019) and fast (12-16 Hz) spindle percent (p-quadratic=0.016) showed inverted U-shaped trajectories, with plateaus after 15y and 19y, respectively. Spindle frequency increased (p-linear<0.001), while spindle power decreased (p-linear<0.001) from 6y to 21y. The trajectories of spindle density, frequency and fast spindle percent diverged between females and males, in whom density plateaued by 14y, fast spindle percent by 16y, and frequency by 18y, while fast spindle percent and spindle frequency continued to increase until 21y in females. Males exper...

Cells in the entorhinal cortex (EC) contain rich spatial information and project strongly to the hippocampus where a cognitive map is supposedly created. These cells range from cells with structured spatial selectivity, such as grid cells in the medial entorhinal cortex (MEC) that are selective to an array of spatial locations that form a hexagonal grid, to weakly spatial cells, such as non-grid cells in the MEC and lateral entorhinal cortex (LEC) that contain spatial information but have no structured spatial selectivity. However, in a small environment, place cells in the hippocampus are generally selective to a single location of the environment, while granule cells in the dentate gyrus of the hippocampus have multiple discrete firing locations but lack spatial periodicity. Given the anatomical connection from the EC to the hippocampus, how the hippocampus retrieves information from upstream EC remains unclear. Here, we propose a unified learning model that can describe the spatial tuning properties of ...