The projection neurons of the striatum, the principal nucleus of the basal ganglia, belong to one of two major pathways: the striatopallidal (indirect) pathway or the striatonigral (direct) pathway. Striatonigral axons project long-distances and encounter ascending (thalamocortical) while coursing alongside descending (corticofugal) tracts as they extend through the internal capsule and cerebral peduncle. These observations suggest that striatal circuitry may help to guide their trajectories. To investigate the developmental contributions of striatonigral axons to internal capsule formation, we have made use of Sox8-EGFP (striatal direct pathway) and Fezf2-TdTomato (corticofugal pathway) BAC transgenic reporter mice in combination with immunohistochemical markers to trace these axonal pathways throughout development. We show that striatonigral axons pioneer the internal capsule and cerebral peduncle and are temporally and spatially well-positioned to provide guidance for corticofugal and thalamocortical ax...

The noradrenergic locus coeruleus (LC) mediates key aspects of arousal, memory, and cognition in structured tasks, but its contribution to naturalistic behavior remains unclear. LC activity is thought to multiplex distinct signals by superimposing sustained (‘tonic’) firing patterns reflecting global brain states, such as arousal and anxiety, and rapidly fluctuating (‘phasic’) bursts signaling discrete behaviorally significant events. Manipulations of the LC noradrenergic system broadly impair social behavior, but the temporal structure of LC firing and its relationship to social interaction is unknown. One possibility is that tonic firing may increase in the presence of social partners; it is also possible that phasic bursts may accompany specific social events. We used chronic in vivo electrophysiology and fiber photometry to measure single unit and population neural activity in LC of freely behaving mice during their interactions with pups. We find that pup retrieval elicits remarkably precise phasic ac...

Decisions to act while pursuing goals in the presence of danger must be made quickly but safely. Premature decisions risk injury or death whereas postponing decisions risk goal loss. Here we show how mice resolve these competing demands. Using microstructural behavioral analyses, we identified the spatiotemporal dynamics of approach-avoidance decisions under motivational conflict in male mice. Then we used cognitive modelling to show that these dynamics reflect the speeded decision-making mechanisms used by humans and non-human primates, with mice trading off decision speed for safety of choice when danger loomed. Using calcium imaging in paraventricular thalamus and optogenetic inhibition of the prelimbic cortex to paraventricular thalamus pathway, we show that this speed-safety trade off occurs because increases in paraventricular thalamus activity increase decision caution, thereby increasing approach-avoid decision times in the presence of danger. Our findings demonstrate that a discrete brain circuit ...

In the olfactory bulb, mitral cells (MCs) display a spontaneous firing that is characterized by bursts of action potentials (APs) intermixed with silent periods. Intra-burst firing frequency and duration are heterogeneous among MCs and increase with membrane depolarization. By using patch clamp recording on rat slices, we dissected out the intrinsic properties responsible of this bursting activity. We showed that the threshold of AP generation dynamically changes as a function of the preceding trajectory of the membrane potential. In fact, the AP threshold became more negative when the membrane was hyperpolarized and had a recovering rate inversely proportional to the membrane repolarization rate. Such variations appeared to be produced by changes in the inactivation state of voltage dependent Na+ channels. Thus, AP initiation was favored by hyperpolarizing events, such as negative membrane oscillations or inhibitory synaptic input. After the first AP, the following fast afterhyperpolarization (fast AHP) b...

The precise regulation of blood-brain barrier (BBB) permeability for immune cells and blood-borne substances is essential to maintain brain homeostasis. Sphingosine-1-phosphate (S1P), a lipid signaling molecule enriched in plasma, is known to affect BBB permeability. Previous studies focused on endothelial S1P receptors 1 and 2, reporting a barrier-protective effect of S1P1 and a barrier-disruptive effect of S1P2. Here, we present novel data characterizing the expression, localization, and function of the S1P receptor 4 (S1P4) on primary brain microvascular endothelial cells (BMECs). Hitherto, the receptor was deemed to be exclusively immune cell associated. We detected a robust expression of S1P4 in homeostatic murine BMECs (MBMECs), bovine BMECs (BBMECs), and porcine BMECs (PBMECs) and pinpointed its localization to abluminal endothelial membranes via immunoblotting of fractionated brain endothelial membrane fragments. Apical S1P treatment of BMECs tightened the endothelial barrier in vitro , whereas bas...

Functional hemispheric lateralization is a basic principle of brain organization. In the auditory domain, the right auditory cortex (AC) determines the pitch direction of continuous auditory stimuli whereas the left AC discriminates gaps in these stimuli. The involved functional interactions between the two sides, mediated by commissural connections, are poorly understood. Here, we selectively disrupted the interhemispheric cross talk from the left to the right primary AC and vice versa using chromophore-targeted laser-induced apoptosis of the respective projection neurons, which make up 6–17% of all AC neurons in Layers III, V, and VI. Following photolysis, male gerbils were trained in a first experimental set to discriminate between rising and falling frequency-modulated (FM) tone sweeps. The acquisition of the task was significantly delayed in lesioned animals of either lesion direction. However, the final discrimination performance and hit rate was lowest for animals with left-side lesioned commissural...

Electrical stimulation of the peripheral nerves of human participants provides a unique opportunity to study the neural determinants of perceptual quality using a causal manipulation. A major challenge in the study of neural coding of touch has been to isolate the role of spike timing—at the scale of milliseconds or tens of milliseconds—in shaping the sensory experience. In the present study, we address this question by systematically varying the pulse frequency (PF) of electrical stimulation pulse trains delivered to the peripheral nerves of seven participants with upper and lower extremity limb loss via chronically implanted neural interfaces. We find that increases in PF lead to systematic increases in perceived frequency, up to ∼50 Hz, at which point further changes in PF have little to no impact on sensory quality. Above this transition frequency, ratings of perceived frequency level off, the ability to discriminate changes in PF is abolished, and verbal descriptors selected to characterize the sensat...

Motor skills learned through practice are consolidated at later time, which can include nighttime, but the time course of motor memory consolidation and its underlying mechanisms remain poorly understood. We investigated neural substrates underlying motor memory consolidation of learned changes in birdsong, a tractable model system for studying neural basis of motor skill learning. Previous studies in male zebra finches and Bengalese finches have demonstrated that adaptive changes in adult song structure learned through a reinforcement paradigm are initially driven by a cortical-basal ganglia circuit, and subsequently consolidated into downstream cortical motor circuitry. However, the time course of the consolidation process, including whether it occurs offline during nighttime or online during daytime, remains unclear and even controversial. Here, we provide in both species experimental evidence of virtually no consolidation of learned vocal changes during nighttime. We demonstrate instead that the consol...

Extensive training can improve performance on almost every visual task, through a process called visual perceptual learning ([He et al., 2021][1]). Visual perceptual learning has been applied to rehabilitate impaired vision for patients with low vision ([He et al., 2021][1]). In addition, visual