Homeostatic plasticity maintains network stability by adjusting excitation, inhibition, or the intrinsic excitability of neurons, but the developmental regulation and coordination of these distinct forms of homeostatic plasticity remains poorly understood. A major contributor to this information gap is the lack of a uniform paradigm for chronically manipulating activity at different developmental stages. To overcome this limitation, we used designer receptors exclusively activated by designer drugs (DREADDs) to directly suppress neuronal activity in layer2/3 (L2/3) of mouse primary visual cortex of either sex at two important developmental timepoints: the classic visual system critical period [CP; postnatal day 24 (P24) to P29], and adulthood (P45 to P55). We show that 24 h of DREADD-mediated activity suppression simultaneously induces excitatory synaptic scaling up and intrinsic homeostatic plasticity in L2/3 pyramidal neurons during the CP, consistent with previous observations using prolonged visual dep...

Oligodendrocytes are vulnerable to genetic and environmental insults and its injury leads to demyelinating diseases. The roles of ErbB receptors in maintaining the CNS myelin integrity are largely unknown. Here, we overactivate ErbB receptors that mediate signaling of either neuregulin (NRG) or epidermal growth factor (EGF) family growth factors and found their synergistic activation caused deleterious outcomes in white matter. Sustained ErbB activation induced by the tetracycline-dependent mouse tool Plp -tTA resulted in demyelination, axonal degeneration, oligodendrocyte precursor cell (OPC) proliferation, astrogliosis, and microgliosis in white matter. Moreover, there was hypermyelination before these inflammatory pathologic events. In contrast, sustained ErbB activation induced by another tetracycline-dependent mouse tool Sox10 +/rtTA caused hypomyelination in the corpus callosum and optic nerve, which appeared to be a developmental deficit and did not associate with OPC regeneration, astrogliosis, or ...

The stop-signal task is a well-established assessment of response inhibition, and in humans, proficiency is linked to dorsal striatum D2 receptor availability. Parkinson's disease (PD) is characterized by changes to efficiency of response inhibition. Here, we studied 17 PD patients (6 female and 11 male) using the stop-signal paradigm in a single-blinded d-amphetamine (dAMPH) study. Participants completed [18F]fallypride positron emission topography (PET) imaging in both placebo and dAMPH conditions. A voxel-wise analysis of the relationship between binding potential (BPND) and stop-signal reaction time (SSRT) revealed that faster SSRT is associated with greater D2-like BPND in the amygdala and hippocampus (right cluster q FDR-corr = 0.026, left cluster q FDR-corr = 0.002). A region of interest (ROI) examination confirmed this association in both the amygdala (coefficient = −48.26, p = 0.005) and hippocampus (coefficient = −104.94, p = 0.007). As healthy dopaminergic systems in the dorsal striatum appear t...

Mutations in some cell adhesion molecules (CAMs) cause abnormal synapse formation and maturation, and serve as one of the potential mechanisms of autism spectrum disorders (ASDs). Recently, DSCAM (Down syndrome cell adhesion molecule) was found to be a high-risk gene for autism. However, it is still unclear how DSCAM contributes to ASD. Here, we show that DSCAM expression was downregulated following synapse maturation, and that DSCAM deficiency caused accelerated dendritic spine maturation during early postnatal development. Mechanistically, the extracellular domain (ECD) of DSCAM interacts with neuroligin1 (NLGN1) to block the NLGN1-neurexin1β (NRXN1β) interaction. DSCAM-ECD was able to rescue spine overmaturation in DSCAM knockdown neurons. Precocious spines in DSCAM-deficient mice showed increased glutamatergic transmission in the developing cortex and induced autism-like behaviors such as social novelty deficits and repetitive behaviors. Thus, DSCAM might be a repressor that prevents premature spine ma...

Parkinson’s disease (PD) is a neurodegenerative disease that includes motor impairments such as tremor, bradykinesia, and postural instability. Although eye movement deficits are commonly found in saccade and pursuit tasks, preservation of oculomotor function has also been reported. Here we investigate specific task and stimulus conditions under which oculomotor function in PD is preserved. Sixteen PD patients and eighteen healthy, age-matched controls completed a battery of movement tasks that included stationary or moving targets eliciting reactive or deliberate eye movements: pro-saccades, anti-saccades, visually-guided pursuit, and rapid go/no-go manual interception. Compared to controls, patients demonstrated systematic impairments in tasks with stationary targets: pro-saccades were hypometric and anti-saccades were incorrectly initiated toward the cued target in about 35% of trials compared to 14% errors in controls. In patients, task errors were linked to short latency saccades, indicating abnormali...

Predicting and organizing patterns of events is important for humans to survive in a dynamically changing world. The motor system has been proposed to be actively, and necessarily, engaged in not only the production but the perception of rhythm by organizing hierarchical timing that influences auditory responses. It is not yet well understood how the motor system interacts with the auditory system to perceive and maintain hierarchical structure in time. This study investigated the dynamic interaction between auditory and motor functional sources during the perception and imagination of musical meters. We pursued this using a novel method combining high-density EEG, EMG and motion capture with independent component analysis (ICA) to separate motor and auditory activity during meter imagery while robustly controlling against covert movement. We demonstrated that endogenous brain activity in both auditory and motor functional sources reflects the imagination of binary and ternary meters in the absence of corr...

Sharp wave ripples (SW-Rs) in the hippocampus are synchronized bursts of hippocampal pyramidal neurons (PyNs), critical for spatial working memory. However, the molecular underpinnings of SW-Rs remain poorly understood. We show that SW-Rs in hippocampal slices from both male and female mice were suppressed by neuregulin 1 (NRG1), an epidermal growth factor whose expression is enhanced by neuronal activity. Pharmacological inhibition of ErbB4, a receptor tyrosine kinase for NRG1, increases SW-R occurrence rate in hippocampal slices. These results suggest an important role of NRG1-ErbB4 signaling in regulating SW-Rs. To further test this notion, we characterized SW-Rs in freely moving male mice, chemical genetic mutant mice, where ErbB4 can be specifically inhibited by the bulky inhibitor 1NMPP1. Remarkably, SW-R occurrence was increased by 1NMPP1. We found that 1NMPP1 increased the firing rate of PyN neurons, yet disrupted PyN neuron dynamics during SW-R events. Furthermore, 1NMPP1 increased SW-R occurrence...

Precise information flow from the hippocampus (HP) to prefrontal cortex (PFC) emerges during early development and accounts for cognitive processing throughout life. On flip side, this flow is selectively impaired in mental illness. In mouse models of psychiatric risk mediated by gene-environment interaction (GE), the prefrontal-hippocampal coupling is disrupted already shortly after birth. While this impairment relates to local miswiring in PFC and HP, it might be also because of abnormal connectivity between the two brain areas. Here, we test this hypothesis by combining in vivo electrophysiology and optogenetics with in-depth tracing of projections and monitor the morphology and function of hippocampal afferents in the PFC of control and GE mice of either sex throughout development. We show that projections from the hippocampal CA1 area preferentially target layer 5/6 pyramidal neurons and interneurons, and to a lesser extent layer 2/3 neurons of prelimbic (PL) subdivision of PFC. In neonatal GE mice, s...

Neuronal activity in the prefrontal cortex (PFC) controls dominance hierarchies in groups of animals. Dopamine (DA) strongly modulates PFC activity mainly through D1 receptors (D1Rs) and D2 receptors (D2Rs). Still, it is unclear how these two subpopulations of DA receptor-expressing neurons in the PFC regulate social dominance hierarchy. Here, we demonstrate distinct roles for prefrontal D1R- and D2R-expressing neurons in establishing social hierarchy, with D1R+ neurons determining dominance whereas D2R+ neurons for the subordinate. Ex vivo whole-cell recordings revealed that the dominant status of male mice correlates with rectifying AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor transmission and stronger excitatory synaptic strength onto D1R+ neurons in PFC pyramidal neurons. In contrast, the submissive status is associated with higher neuronal excitability in D2R+ neurons. Moreover, simultaneous manipulations of synaptic efficacy of D1R+ neurons in dominant male mice and neuronal e...

Introduction: The hippocampus is a locus of working memory (WM) with anterior and posterior subregions that differ in their transcriptional and external connectivity patterns. However, the involvement and functional connections between these subregions in WM processing are poorly understood. Methods: To address these issues, we recorded intracranial EEG from the anterior and the posterior hippocampus in human (7 females and 7 males) who maintained a set of letters in their WM. Results: We found that WM maintenance was accompanied by elevated low-frequency activity in both the anterior and posterior hippocampus and by increased theta/alpha band (3-12 Hz) phase synchronization between anterior and posterior subregions. Cross-frequency and Granger prediction analyses consistently showed that the correct WM trials were associated with theta/alpha band-coordinated unidirectional influence from the posterior to the anterior hippocampus. In contrast, WM errors were associated with bidirectional interactions bet...