A neural substrate of sex-dependent modulation of motivation.

While there is emerging evidence of sex differences in decision-making behavior, the neural substrates that underlie such differences remain largely unknown. Here we demonstrate that in mice performing a value-based decision-making task, while choices are similar between the sexes, motivation to engage in the task is modulated by action value more strongly in females than in males. Inhibition of activity in anterior cingulate cortex (ACC) neurons that project to the dorsomedial striatum (DMS) preferentially disrupts this relationship between value and motivation in females, without affecting choice in either sex. In line with these effects, in females compared to males, ACC-DMS neurons have stronger representations of negative outcomes and more neurons are active when the value of the chosen option is low. By contrast, the representation of each choice is similar between the sexes. Thus, we identify a neural substrate that contributes to sex-specific modulation of motivation by value.

Imaging the construction of capillary networks in the neonatal mouse brain.

Capillary networks are essential for distribution of blood flow through the brain, and numerous other homeostatic functions, including neurovascular signal conduction and blood-brain barrier integrity. Accordingly, the impairment of capillary architecture and function lies at the root of many brain diseases. Visualizing how brain capillary networks develop in vivo can reveal innate programs for cerebrovascular growth and repair. Here, we use longitudinal two-photon imaging through noninvasive thinned skull windows to study a burst of angiogenic activity during cerebrovascular development in mouse neonates. We find that angiogenesis leading to the formation of capillary networks originated exclusively from cortical ascending venules. Two angiogenic sprouting activities were observed: 1) early, long-range sprouts that directly connected venules to upstream arteriolar input, establishing the backbone of the capillary bed, and 2) short-range sprouts that contributed to expansion of anastomotic connectivity within the capillary bed. All nascent sprouts were prefabricated with an intact endothelial lumen and pericyte coverage, ensuring their immediate perfusion and stability upon connection to their target vessels. The bulk of this capillary expansion spanned only 2 to 3 d and contributed to an increase of blood flow during a critical period in cortical development.

Three-dimensional ultrastructure of the brain pericyte-endothelial interface.

Pericytes and endothelial cells share membranous interdigitations called "peg-and-socket" interactions that facilitate their adhesion and biochemical crosstalk during vascular homeostasis. However, the morphology and distribution of these ultrastructures have remained elusive. Using a combination of 3D electron microscopy techniques, we examined peg-and-socket interactions in mouse brain capillaries. We found that pegs extending from pericytes to endothelial cells were morphologically diverse, exhibiting claw-like morphologies at the edge of the cell and bouton-shaped swellings away from the edge. Reciprocal endothelial pegs projecting into pericytes were less abundant and appeared as larger columnar protuberances. A large-scale 3D EM data set revealed enrichment of both pericyte and endothelial pegs around pericyte somata. The ratio of pericyte versus endothelial pegs was conserved among the pericytes examined, but total peg abundance was heterogeneous across cells. These data show considerable investment between pericytes and endothelial cells, and provide morphological evidence for pericyte somata as sites of enriched physical and biochemical interaction.

A Comparison of Dopaminergic and Cholinergic Populations Reveals Unique Contributions of VTA Dopamine Neurons to Short-Term Memory.

We systematically compare the contributions of two dopaminergic and two cholinergic ascending populations to a spatial short-term memory task in rats. In ventral tegmental area dopamine (VTA-DA) and nucleus basalis cholinergic (NB-ChAT) populations, trial-by-trial fluctuations in activity during the delay period relate to performance with an inverted-U, despite the fact that both populations have low activity during that time. Transient manipulations reveal that only VTA-DA neurons, and not the other three populations we examine, contribute causally and selectively to short-term memory. This contribution is most significant during the delay period, when both increases and decreases in VTA-DA activity impair short-term memory. Our results reveal a surprising dissociation between when VTA-DA neurons are most active and when they have the biggest causal contribution to short-term memory, and they also provide support for classic ideas about an inverted-U relationship between neuromodulation and cognition.

Specialized coding of sensory, motor and cognitive variables in VTA dopamine neurons.

There is increased appreciation that dopamine neurons in the midbrain respond not only to reward1 and reward-predicting cues1,2, but also to other variables such as the distance to reward3, movements4-9 and behavioural choices10,11. An important question is how the responses to these diverse variables are organized across the population of dopamine neurons. Whether individual dopamine neurons multiplex several variables, or whether there are subsets of neurons that are specialized in encoding specific behavioural variables remains unclear. This fundamental question has been difficult to resolve because recordings from large populations of individual dopamine neurons have not been performed in a behavioural task with sufficient complexity to examine these diverse variables simultaneously. Here, to address this gap, we used two-photon calcium imaging through an implanted lens to record the activity of more than 300 dopamine neurons from the ventral tegmental area of the mouse midbrain during a complex decision-making task. As mice navigated in a virtual-reality environment, dopamine neurons encoded an array of sensory, motor and cognitive variables. These responses were functionally clustered, such that subpopulations of neurons transmitted information about a subset of behavioural variables, in addition to encoding reward. These functional clusters were spatially organized, with neighbouring neurons more likely to be part of the same cluster. Together with the topography between dopamine neurons and their projections, this specialization and anatomical organization may aid downstream circuits in correctly interpreting the wide range of signals transmitted by dopamine neurons.