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Summary: There has never been a wholesale way of identifying neurons that are monosynaptically connected either to some other cell group or, especially, to a single cell. The best available tools, transsynaptic tracers, are unable to distinguish weak direct connections from strong indirect ones. Furthermore, no tracer has proven potent enough to label any connected neurons whatsoever when starting from a single cell. Here we present a transsynaptic tracer that crosses only one synaptic step, unambiguously identifying cells directly presynaptic to the starting population. Based on rabies virus, it is genetically targetable, allows high-level expression of any gene of interest in the synaptically coupled neurons, and robustly labels connections made to single cells. This technology should enable a far more detailed understanding of neural connectivity than has previously been possible. [Copyright &y& Elsevier]

Balanced activity of canonical direct D1 and indirect D2 basal ganglia pathways is considered a core requirement for normal movement, and their imbalance is an etiologic factor in movement and neuropsychiatric disorders. We present evidence for a conceptually equivalent pair of direct D1 and indirect D2 pathways that arise from striatal projection neurons (SPNs) of the striosome compartment rather than from SPNs of the matrix, as do the canonical pathways. These striosomal D1 (S-D1) and D2 (S-D2) pathways target substantia nigra dopamine-containing neurons instead of basal ganglia motor output nuclei. They modulate movement with net effects opposite to those exerted by the canonical pathways: S-D1 is net inhibitory and S-D2 is net excitatory. The S-D1 and S-D2 circuits likely influence motivation for learning and action, complementing and reorienting canonical pathway modulation. A major conceptual reformulation of the classic direct-indirect pathway model of basal ganglia function is needed, as well as reconsideration of the effects of D2-targeting therapeutic drugs. • Direct S-D1 and indirect S-D2 striosomal pathways target SNpc dopamine cells • The S-D2 indirect pathway targets a distinct central zone of the GPe • Stimulation of S-D2 increases, of S-D1 decreases, striatal dopamine and movement • S-D1-S-D2 and canonical D1-D2 pathways have opposite effects on voluntary movement Lazaridis et al. delineate a previously unrecognized pair of striosomal direct D1 and indirect D2 circuits that target substantia nigra dopamine-containing neurons, controllers of mood, action, and reinforcement learning. These striosomal circuits have effects opposing those of the canonical D1-direct/D2-indirect pathways, likely modulating them. [ABSTRACT FROM AUTHOR]

A comprehensive characterization of neuronal cell types, their distributions, and patterns of connectivity is critical for understanding the properties of neural circuits and how they generate behaviors. Here we review the experiences of the BRAIN Initiative Cell Census Consortium, ten pilot projects funded by the U.S. BRAIN Initiative, in developing, validating, and scaling up emerging genomic and anatomical mapping technologies for creating a complete inventory of neuronal cell types and their connections in multiple species and during development. These projects lay the foundation for a larger and longer-term effort to generate whole-brain cell atlases in species including mice and humans. [ABSTRACT FROM AUTHOR]

Extracting the valence of environmental cues is critical for animals' survival. How valence in sensory signals is encoded and transformed to produce distinct behavioral responses remains not well understood. Here, we report that the mouse pontine central gray (PCG) contributes to encoding both negative and positive valences. PCG glutamatergic neurons were activated selectively by aversive, but not reward, stimuli, whereas its GABAergic neurons were preferentially activated by reward signals. The optogenetic activation of these two populations resulted in avoidance and preference behavior, respectively, and was sufficient to induce conditioned place aversion/preference. Suppression of them reduced sensory-induced aversive and appetitive behaviors, respectively. These two functionally opponent populations, receiving a broad range of inputs from overlapping yet distinct sources, broadcast valence-specific information to a distributed brain network with distinguishable downstream effectors. Thus, PCG serves as a critical hub to process positive and negative valences of incoming sensory signals and drive valence-specific behaviors with distinct circuits. [Display omitted] • PCG glutamate and GABA neurons encode negative and positive valence, respectively • These neurons mediate aversion and appetitive behaviors, respectively • Input-output organizations of PCG glutamate and GABA neurons are characterized • PCG relays valence information into a globally distributed network Xiao et al. find that pontine central gray (PCG) contributes to encoding positive and negative valences through the activity of its GABAergic and glutamatergic neurons, respectively, which mediate sensory-induced reward- and aversion-related behaviors. Thus, PCG may serve as a critical hub for the bottom-up processing of sensory valence preceding the limbic system. [ABSTRACT FROM AUTHOR]

A major pathological hallmark of neurodegenerative diseases, including Alzheimer's, is a significant reduction in the white matter connecting the two cerebral hemispheres, as well as in the correlated activity between anatomically corresponding bilateral brain areas. However, the underlying circuit mechanisms and the cognitive relevance of cross-hemispheric (CH) communication remain poorly understood. Here, we show that novelty discrimination behavior activates CH neurons and enhances homotopic synchronized neural oscillations in the visual cortex. CH neurons provide excitatory drive required for synchronous neural oscillations between hemispheres, and unilateral inhibition of the CH circuit is sufficient to impair synchronous oscillations and novelty discrimination behavior. In the 5XFAD and Tau P301S mouse models, CH communication is altered, and novelty discrimination is impaired. These data reveal a hitherto uncharacterized CH circuit in the visual cortex, establishing a causal link between this circuit and novelty discrimination behavior and highlighting its impairment in mouse models of neurodegeneration. [Display omitted] • Novelty discrimination enhances neuronal activity in cross-hemispheric circuits • The visual cortex comprises a functional bidirectional CH circuit • CH neurons are indispensable for homotopic neural oscillations • CH communication is altered in 5XFAD and Tau P301S mice Adaikkan et al. discuss how a functional circuit comprised of cross-hemispheric neurons in the homotopic visual cortex is required for novelty discrimination and how alterations in this circuit lead to impaired discrimination-dependent tasks in mouse models of neurodegeneration. [ABSTRACT FROM AUTHOR]

Summary Sensory computations performed in the neocortex involve layer six (L6) cortico-cortical (CC) and cortico-thalamic (CT) signaling pathways. Developing an understanding of the physiological role of these circuits requires dissection of the functional specificity and connectivity of the underlying individual projection neurons. By combining whole-cell recording from identified L6 principal cells in the mouse primary visual cortex (V1) with modified rabies virus-based input mapping, we have determined the sensory response properties and upstream monosynaptic connectivity of cells mediating the CC or CT pathway. We show that CC-projecting cells encompass a broad spectrum of selectivity to stimulus orientation and are predominantly innervated by deep layer V1 neurons. In contrast, CT-projecting cells are ultrasparse firing, exquisitely tuned to orientation and direction information, and receive long-range input from higher cortical areas. This segregation in function and connectivity indicates that L6 microcircuits route specific contextual and stimulus-related information within and outside the cortical network. [ABSTRACT FROM AUTHOR]

Neuropsychiatric disorders are often accompanied by cognitive impairments/intellectual disability (ID). It is not clear whether there are converging mechanisms underlying these debilitating impairments. We found that many autism and schizophrenia risk genes are expressed in the anterodorsal subdivision (AD) of anterior thalamic nuclei, which has reciprocal connectivity with learning and memory structures. CRISPR-Cas9 knockdown of multiple risk genes selectively in AD thalamus led to memory deficits. While the AD is necessary for contextual memory encoding, the neighboring anteroventral subdivision (AV) regulates memory specificity. These distinct functions of AD and AV are mediated through their projections to retrosplenial cortex, using differential mechanisms. Furthermore, knockdown of autism and schizophrenia risk genes PTCHD1 , YWHAG , or HERC1 from AD led to neuronal hyperexcitability, and normalization of hyperexcitability rescued memory deficits in these models. This study identifies converging cellular to circuit mechanisms underlying cognitive deficits in a subset of neuropsychiatric disease models. [Display omitted] • AD thalamus is necessary for memory encoding • AV thalamus regulates memory specificity • Knockdown of autism and schizophrenia risk genes from AD leads to cognitive deficits • Disease models exhibit converging cellular and circuit mechanisms in AD Neuropsychiatric disorders are often accompanied by cognitive impairments. Roy et al. report that the knockdown of several autism and schizophrenia risk genes from anterodorsal thalamus leads to hyperexcitability and cognitive deficits. Normalization of hyperexcitability rescues cognitive deficits across models, revealing a converging mechanism underlying cognitive deficits. [ABSTRACT FROM AUTHOR]