To deconstruct the architecture and function of brain circuits, it is necessary to generate maps of the neuronal connectivity and activity on a whole brain scale. New methods now enable large-scale mapping of the mouse brain at cellular and subcellular resolution. We developed a framework to automatically annotate, analyze, visualize, and easily share whole-brain data at cellular resolution, based on a scale-invariant and interactive mouse brain atlas. This framework enables connectivity and mapping projects in individual laboratories, across imaging platforms, as well as multiplexed quantitative information on the molecular identity of single neurons. As a proof of concept, we generated a comparative connectivity map of five major neuron types in the corticostriatal circuit, as well as an activity-based map to identify hubs mediating the behavioral effects of cocaine. Thus, this computational framework provides the necessary tools to generate brain maps that integrate data from connectivity, neuron identity and function.

Brain maps are essential for integrating information and interpreting the structure-function relationship of circuits and behavior. We aimed to generate a systematic classification of the adult mouse brain based purely on the unbiased identification of spatially defining features by employing whole-brain spatial transcriptomics. We found that the molecular information was sufficient to deduce the complex and detailed neuroanatomical organization of the brain. The unsupervised (non-expert, data-driven) classification revealed new area- and layer-specific subregions, for example in isocortex and hippocampus, and new subdivisions of striatum. The molecular atlas further supports the characterization of the spatial identity of neurons from their single-cell RNA profile, and provides a resource for annotating the brain using a minimal gene set—a brain palette. In summary, we have established a molecular atlas to formally define the spatial organization of brain regions, including the molecular code for mapping and targeting of discrete neuroanatomical domains.

Encoding and predicting aversive events are critical functions of circuits that support survival and emotional well-being. Maladaptive circuit changes in emotional valence processing can underlie the pathophysiology of affective disorders. The lateral habenula (LHb) has been linked to aversion and mood regulation through modulation of the dopamine and serotonin systems. We have defined the identity and function of glutamatergic (Vglut2) control of the LHb, comparing the role of inputs originating in the globus pallidus internal segment (GPi), and lateral hypothalamic area (LHA), respectively. We found that LHb-projecting LHA neurons, and not the proposed GABA/glutamate co-releasing GPi neurons, are responsible for encoding negative value. Monosynaptic rabies tracing of the presynaptic organization revealed a predominantly limbic input onto LHA Vglut2 neurons, while sensorimotor inputs were more prominent onto GABA/glutamate co-releasing GPi neurons. We further recorded the activity of LHA Vglut2 neurons, by imaging calcium dynamics in response to appetitive versus aversive events in conditioning paradigms. LHA Vglut2 neurons formed activity clusters representing distinct reward or aversion signals, including a population that responded to mild foot shocks and predicted aversive events. We found that the LHb-projecting LHA Vglut2 neurons encode negative valence and rapidly develop a prediction signal for negative events. These findings establish the glutamatergic LHA-LHb circuit as a critical node in value processing.

Highlights d Genetic labeling of Oprm1+ cells in striatum visualizes patches d Single-nucleus RNA-seq defines identity of neuron subtypes in striatum d The striatum is subdivided based on a spatiomolecular code

Brain maps are essential for integrating information and interpreting the structure-function relationship of circuits and behavior. We aimed to generate a systematic classification of the adult mouse brain organization based on unbiased extraction of spatially-defining features. Applying whole-brain spatial transcriptomics, we captured the gene expression signatures to define the spatial organization of molecularly discrete subregions. We found that the molecular code contained sufficiently detailed information to directly deduce the complex spatial organization of the brain. This unsupervised molecular classification revealed new area-and layer-specific subregions, for example in isocortex and hippocampus, and a new division of striatum.

The most frequently described drugs in the treatment of mood disorders are selective serotonin reuptake and monoamine oxidase (MAO) inhibitors, enhancing serotonin levels in the brain. However, side-effects have been reported for these drugs. Because serotonin levels in the brain are dependent on the availability of the food-derived precursor tryptophan, foods such as chicken, soyabeans, cereals, tuna, nuts and bananas may serve as an alternative to improve mood and cognition. Here we discuss the effects of high-or low-tryptophancontaining food, as well as plant extracts with a modest monoamine reuptake and MAO-A inhibition functional profile, on mood and cognition in healthy and vulnerable human subjects and rodents. Together the studies suggest that there is an inverted U-shaped curve for plasma tryptophan levels, with low and too high tryptophan levels impairing cognition, and moderate to high tryptophan levels improving cognition. This relationship is found for both healthy and vulnerable subjects. Whereas this relationship may also exist for mood, the inverted U-shaped curve for plasma tryptophan levels and mood may be based on different tryptophan concentrations in healthy v. vulnerable individuals. Animal studies are emerging and allow further understanding of effects and the mode of action of food-derived serotonergic components on mood, cognition and mechanisms. Ultimately, insight into the concentrations of tryptophan and other serotonergic components in food having beneficial effects on mood and cognition in healthy, but particularly vulnerable, subjects may support well-being in our highly demanding society.

The functional significance of the interhemispheric projections on the basal ganglia level is poorly understood. Insofar as the anatomical evidence for crossing projections between basal ganglia nuclei is sparse, whereas tracing studies demonstrated important crossing projections from the pedunculopontine nucleus (PPN) to the basal ganglia, it is suggested that the PPN might play a key role in interhemispheric regulation of basal ganglia activity. The present study was performed to assess changes in neuronal activity of ipsilateral and contralateral subthalamic nucleus (STN), substantia nigra pars reticulata (SNr), and PPN in the unilateral 6-hydroxydopamine (6-OHDA) rat model of advanced PD under urethane anesthesia. After unilateral lesioning of the SNc, the firing rate of contralateral STN neurons significantly increased from 10.9 +/- 1.0 spikes/sec (mean +/- SEM) to 16.3 +/- 1.5 spikes/sec. Similarly, the firing rate of contralateral SNr neurons significantly increased from 19.4 +/- 1.2 to 25.7 +/- 1.9 spikes/sec, and the firing rate of contralateral PPN neurons significantly increased from 10.6 +/- 0.8 to 13.9 +/- 1.1 spikes/sec. The observed activity changes in contralateral STN, SNr, and PPN are similar to those induced in the corresponding nuclei of the hemisphere ipsilateral to the nigrostriatal degeneration. Based on previous, predominantly anatomical data, the results of the present study suggest that the PPN on the lesioned side is at the origin of changes in the activity of STN and SNr on the contralateral hemisphere, because of its crossing efferent projections.

Inhibitory interneurons expressing parvalbumin (PV) in the prefrontal cortex (PFC) are central to excitatory/inhibitory (E/I) balance, generation of gamma oscillations, and cognition. Dysfunction of PV interneurons disrupts information processing and cognitive behavior. Tyrosine receptor kinase B (trkB) signaling is known to regulate the differentiation and maturation of cortical PV interneurons during development, but is also suggested to be involved in the activity and network functions of PV interneurons in the adult brain. Using a novel viral strategy for cell-type and region-specific expression of a dominant negative trkB in adult mice, we show that reduced trkB signaling in PV interneurons in the PFC leads to pronounced morphological, physiological, and behavioral changes. Our results provide evidence for a critical role of trkB signaling in the function of PV interneurons in the adult brain, local network activities central to prefrontal circuit dynamics, and cognitive behavior..