The external pallidum (globus pallidus pars externa [GPe]) plays a central role for basal ganglia functions and dynamics and, consequently, has been included in most computational studies of the basal ganglia. These studies considered the GPe as a homogeneous neural population. However, experimental studies have shown that the GPe contains at least two distinct cell types (prototypical and arkypallidal cells). In this work, we provide in silico insight into how pallidal heterogeneity modulates dynamic regimes inside the GPe and how they affect the GPe response to oscillatory input. We derive a mean-field model of the GPe system from a microscopic spiking neural network of recurrently coupled prototypical and arkypallidal neurons. Using bifurcation analysis, we examine the influence of dopamine-dependent changes of intrapallidal connectivity on the GPe dynamics. We find that increased self-inhibition of prototypical cells can induce oscillations, whereas increased inhibition of prototypical cells by arkypal...

Nina L. Kikel-Coury, Lauren A. Green, Evan L. Nichols, Abigail M. Zellmer, Sanjana Pai, et al. (see pages [6617–6636][1]) The brain and spinal cord are surrounded and protected by a multilayered sheath composed of specialized extracellular matrix (basement membrane), glial processes (forming the

Paternal care plays a critical role in the development of brain and behaviors in offspring in monogamous species. However, the neurobiological mechanisms, especially the neuronal circuity, underlying paternal care is largely unknown. Using socially monogamous male mandarin voles ( Microtus mandarinus ) with high levels of paternal care, we found that paraventricular nucleus of the hypothalamus (PVN) to ventral tegmental area (VTA) or nucleus accumbens (NAc) oxytocin (OT) neurons are activated during paternal care. Chemogenetic activation/inhibition of the PVN OT projection to VTA promoted/decreased paternal care, respectively. Chemogenetic inhibition of the PVN to VTA OT pathway reduced dopamine (DA) release in the NAc of male mandarin voles during licking and grooming of pups as revealed by in vivo fiber photometry. Optogenetic activation/inhibition of the VTA to NAc DA pathway possibly enhanced/suppressed paternal behaviors, respectively. Furthermore, chemogenetic activation/inhibition of PVN to NAc OT c...

Animals precisely coordinate their left and right limbs for various adaptive purposes. While the left and right limbs are clearly controlled by different cortical hemispheres, the neural mechanisms that determine the action sequence between them remains elusive. Here, we have established a novel head-fixed bimanual-press (biPress) sequence task in which mice sequentially press left and right pedals with their forelimbs in a pre-determined order. Using this motor task, we found that the motor cortical neurons responsible for the first press also generate independent motor signals for the second press by the opposite forelimb during the movement transitions between forelimbs. Projection-specific calcium imaging and optogenetic manipulation revealed these motor signals are transferred from one motor cortical hemisphere to the other via cortico-cortical projections. Together, our results suggest the motor cortices coordinate sequential bimanual movements through cortico-cortical pathways. Significant statemen...

The principal neurons of the striatum – the spiny projection neurons (SPNs) – make inhibitory synaptic connections with each other via collaterals of their main axon, forming a local lateral inhibition network. Serotonin, acting via the 5-HT1B receptor, modulates neurotransmitter release from SPN terminals in striatal output nuclei, but the role of 5-HT1B receptors in lateral inhibition among SPNs in the striatum is unknown. Here we report the effects of 5-HT1B receptor activation on lateral inhibition in the mouse striatum. Whole-cell recordings were made from SPNs in acute brain slices of either sex, while optogenetically activating presynaptic SPNs or fast-spiking interneurons (FSIs). Activation of 5-HT1B receptors significantly reduced the amplitude of inhibitory postsynaptic currents (IPSCs) evoked by optical stimulation of both direct and indirect pathway SPNs. This reduction was blocked by application of a 5-HT1B receptor antagonist. Activation of 5-HT1B receptors did not reduce the amplitude of IPS...

Chronic itch is a troublesome condition and often difficult to cure. Emerging evidence suggests that the periaqueductal gray-rostral ventromedial medulla (PAG-RVM) pathway may play an important role in regulation of itch, but the cellular organization and molecular mechanisms remain incompletely understood. Here, we report that a group of RVM neurons distinctively express the G protein-coupled estrogen receptor (GPER), which mediates descending inhibition of itch. We found that GPER+ neurons in RVM were activated in chronic itch conditions in rats and mice. Selective ablation or chemogenetic suppression of RVM GPER+ neurons resulted in mechanical alloknesis and increased scratching in response to pruritogens, whereas chemogenetic activation of GPER+ neurons abrogated itch responses, indicating that GPER+ neurons are antipruritic. Moreover, GPER-deficient mice and rats of either sex exhibited hypersensitivity to mechanical and chemical itch, a phenotype reversible by μ type opioid receptor (MOR) antagonism....

The ability of the adult human brain to develop function following correction of congenital deafferentation is controversial. Specifically, cases of recovery from congenital visual deficits are rare. CNGA3 -achromatopsia is a congenital hereditary disease caused by cone-photoreceptor dysfunction, leading to impaired acuity, photoaversion, and complete color blindness. Essentially, these patients have rod-driven vision only, seeing the world in blurry shades of grey. We use the uniqueness of this rare disease, in which the cone-photoreceptors and afferent fibers are preserved but do not function, as a model to study cortical visual plasticity. We had the opportunity to study two CNGA3-achromatopsia adults (one female) before and after ocular gene augmentation therapy. Alongside behavioral visual tests, we used novel fMRI based measurements to assess participants’ early-visual population receptive-field sizes and color regions. Behaviorally, minor improvements were observed including reduction in photoaversi...

A precise sequence of axon guidance events is required for the development of the ocular motor system. Three cranial nerves grow toward, and connect with, six extraocular muscles in a stereotyped pattern, to control eye movements. The signaling protein alpha2-chimaerin (α2-CHN) plays a pivotal role in the formation of the ocular motor system; mutations in CHN1 , encoding α2-CHN, cause the human eye movement disorder Duane Retraction Syndrome (DRS). Our research has demonstrated that the manipulation of α2-chn signaling in the zebrafish embryo leads to ocular motor axon wiring defects, although the signaling cascades regulated by α2-chn remain poorly understood. Here, we demonstrate that several cytoskeletal regulatory proteins—collapsin response mediator protein 2 (CRMP2; encoded by the gene dpysl2 ), stathmin1, and stathmin 2—bind to α2-CHN. dpysl2 , stathmin1 , and especially stathmin2 are expressed by ocular motor neurons. We find that the manipulation of dpysl2 and of stathmins in zebrafish larvae lead...

The development, persistence and relapse of drug addiction require drug memory that generally develops with drug administration-paired contextual stimuli. Adult hippocampal neurogenesis (AHN) contributes to cocaine memory formation; however, the underlying mechanism remains unclear. Male mice hippocampal expression of Tau was significantly decreased during the cocaine-associated memory formation. Genetic overexpression of four microtubule-binding repeats Tau (4R Tau) in the mice hippocampus disrupted cocaine memory by suppressing AHN. Furthermore, 4R Tau directly interacted with phosphoinositide 3-kinase (PI3K)-p85 and impaired its nuclear translocation and PI3K-AKT signaling, processes required for hippocampal neuron proliferation. Collectively, 4R Tau modulates cocaine memory formation by disrupting AHN, suggesting a novel mechanism underlying cocaine memory formation and provide a new strategy for the treatment of cocaine addiction. SIGNIFICANCE STATEMENT Drug memory that generally develops with drug-p...

In the article “Patch-seq: Past, Present, and Future,” by Marcela Lipovsek, Cedric Bardy, Cathryn R. Cadwell, Kristen Hadley, Dmitry Kobak, and Shreejoy J. Tripathy, which appeared on pages [937–946][1] of the February 3, 2021 issue, there was a typo on page 940. The text, “…following