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...

Duchenne muscular dystrophy (DMD), the most common form of childhood muscular dystrophy, is caused by mutations in the dystrophin gene. In addition to debilitating muscle degeneration, patients display a range of cognitive deficits thought to result from the loss of dystrophin normally expressed in the brain. While the function of dystrophin in muscle tissue is well characterized, its role in the brain is still poorly understood. The highest expression of dystrophin in the mouse brain is in cerebellar Purkinje cells (PCs), where it colocalizes with GABAA receptor clusters. Using ex vivo electrophysiological recordings from connected molecular layer interneuron (MLI)–PC pairs, we investigated changes in inhibitory synaptic transmission caused by dystrophin deficiency. In male mdx mice (which lack long-form dystrophin), we found that responses at MLI–PC pairs were reduced by ∼60% because of both decreased quantal response amplitude and a reduced number of functional vesicle release sites. Using electron micr...

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...

Repeated pairing of a drug with a neutral stimulus, such as a cue or context, leads to the attribution of the drug's reinforcing properties to that stimulus, and exposure to that stimulus in the absence of the drug can elicit drug-seeking. A principal role for the NAc in the response to drug-associated stimuli has been well documented. Direct and indirect pathway medium spiny neurons (dMSNs and iMSNs) have been shown to bidirectionally regulate cue-induced heroin-seeking in rats expressing addiction-like phenotypes, and a shift in NAc activity toward the direct pathway has been shown in mice following cocaine conditioned place preference (CPP). However, how NAc signaling guides heroin CPP, and whether heroin alters the balance of signaling between dMSNs and iMSNs, remains unknown. Moreover, the role of NAc dopamine signaling in heroin reinforcement is unclear. Here, we integrate fiber photometry for in vivo monitoring of dopamine and dMSN/iMSN calcium activity with a heroin CPP procedure in rats to begin t...

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...

Candler Paige, Isabel Plasencia-Fernandez, Moeno Kume, Melina Papalampropoulou-Tsiridou, Louis-Etienne Lorenzo, et al. (see pages [1930–1944][1]) The molecular and cellular mechanisms of pain are somewhat different in males and females. In rodents, for example, spinal microglia are required for

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