Layer 6 corticothalamic (L6 CT) neurons are in a strategic position to control sensory input to the neocortex, yet we understand very little about their functions. Apart from studying their anatomical, physiological and synaptic properties, most recent efforts have focused on the activity-dependent influences CT cells can exert on thalamic and cortical neurons through causal optogenetic manipulations. However, few studies have attempted to study them during behavior. To address this gap, we performed juxtacellular recordings from optogenetically identified CT neurons in whisker-related primary somatosensory cortex (wS1) of awake, head-fixed mice (either sex) free to rest quietly or self-initiate bouts of whisking and locomotion. We found a rich diversity of response profiles exhibited by CT cells. Their spiking patterns were either modulated by whisking-related behavior (∼28%) or not (∼72%). Whisking-responsive neurons exhibited either increases, activated-type, or decreases in firing rates, suppressed-typ...

Advances in neuroscience have led to the emergence of two complementary theories of neural information processing. First, the “Bayesian brain hypothesis” proposes that the brain actively predicts and represents incoming sensory information as probabilities that are updated in a near-optimal

The need to sleep is sensed and discharged in a poorly understood process that is homeostatically controlled over time. In flies, different contributions to this process have been attributed to peripheral ppk and central brain neurons, with the former serving as hypothetical inputs to the sleep homeostat and the latter reportedly serving as the homeostat itself. Here we re-evaluate these distinctions in light of new findings using female flies. First, activating neurons targeted by published ppk and brain drivers elicits similar phenotypes, namely, sleep deprivation followed by rebound sleep. Second, inhibiting activity or synaptic output with one type of driver suppresses sleep homeostasis induced using the other type of driver. Third, drivers previously used to implicate central neurons in sleep homeostasis unexpectedly also label ppk neurons. Fourth, activating only this subset of colabeled neurons is sufficient to elicit sleep homeostasis. Thus, many published contributions of central neurons to sleep ...

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice ...

In patch foraging tasks, animals must decide whether to remain with a depleting resource or to leave it in search of a potentially better source of reward. In such tasks, animals consistently follow the general predictions of optimal foraging theory (the marginal value theorem; MVT): to leave a patch when the reward rate in the current patch depletes to the average reward rate across patches. Prior studies implicate an important role for the anterior cingulate cortex (ACC) in foraging decisions based on MVT: within single trials, ACC activity increases immediately preceding foraging decisions, and across trials, these dynamics are modulated as the value of staying in the patch depletes to the average reward rate. Here, we test whether these activity patterns reflect dynamic encoding of decision-variables and whether these signals are directly involved in decision-making. We developed a leaky accumulator model based on the MVT that generates estimates of decision variables within and across trials, and test...

Alzheimer's disease (AD) is histopathologically characterized by Aβ plaques and the accumulation of hyperphosphorylated Tau species, the latter also constituting key hallmarks of primary tauopathies. Whereas Aβ is produced by amyloidogenic APP processing, APP processing along the competing nonamyloidogenic pathway results in the secretion of neurotrophic and synaptotrophic APPsα. Recently, we demonstrated that APPsα has therapeutic effects in transgenic AD model mice and rescues Aβ-dependent impairments. Here, we examined the potential of APPsα to mitigate Tau-induced synaptic deficits in P301S mice (both sexes), a widely used mouse model of tauopathy. Analysis of synaptic plasticity revealed an aberrantly increased LTP in P301S mice that could be normalized by acute application of nanomolar amounts of APPsα to hippocampal slices, indicating a homeostatic function of APPsα on a rapid time scale. Further, AAV-mediated in vivo expression of APPsα restored normal spine density of CA1 neurons even at stages of...

Sophie Belin, Bruce A. Maki, James Catlin, Benjamin A. Rein, and Gabriela K. Popescu (see pages [5672–5680][1]) NMDA receptors (NMDARs) are uniquely suited to mediate activity-dependent synaptic activity because their activation requires both ligand (glutamate) binding and membrane

Adolescence is characterized by the maturation of cortical microstructure and connectivity supporting complex cognition and behavior. Axonal myelination influences brain connectivity during development by enhancing neural signaling speed and inhibiting plasticity. However, the maturational timing of cortical myelination during human adolescence remains poorly understood. Here, we take advantage of recent advances in high-resolution cortical T1w/T2w mapping methods, including principled correction of B1+ transmit field effects, using data from the Human Connectome Project in Development (HCP-D; N = 628, ages 8–21). We characterize microstructural changes relevant to myelination by estimating age-related differences in T1w/T2w throughout the cerebral neocortex from childhood to early adulthood. We apply Bayesian spline models and clustering analysis to demonstrate graded variation in age-dependent cortical T1w/T2w differences that are correlated with the sensorimotor-association (S-A) axis of cortical organi...

Neurobiological evidence in rodents indicates that threat extinction incorporates reward neurocircuitry. Consequently, incorporating reward associations with an extinction memory may be an effective strategy to persistently attenuate threat responses. Moreover, while there is considerable research on the short-term effects of extinction strategies in humans, the long-term effects of extinction are rarely considered. In a within-subjects fMRI study with both female and male participants, we compared counterconditioning (CC; a form of rewarded-extinction) to standard extinction at recent (24 h) and remote (approximately one month) retrieval tests. Relative to standard extinction, rewarded extinction diminished 24-h relapse of arousal and threat expectancy, and reduced activity in brain regions associated with the appraisal and expression of threat (e.g., thalamus, insula, periaqueductal gray). The retrieval of reward-associated extinction memory was accompanied by functional connectivity between the amygdala...

Sensory perception and memory are enhanced during restricted phases of ongoing brain rhythms, but whether voluntary movement is constrained by brain rhythm phase is not known. Voluntary movement requires motor commands to be released from motor cortex (M1) and transmitted to spinal motoneurons and effector muscles. Here, we tested the hypothesis that motor commands are preferentially released from M1 during circumscribed phases of ongoing sensorimotor rhythms. Healthy humans of both sexes performed a self-paced finger movement task during electroencephalography (EEG) and electromyography (EMG) recordings. We first estimated the time of motor command release preceding each finger movement by subtracting individually measured corticomuscular transmission latencies from EMG-determined movement onset times. Then, we determined the phase of ipsilateral and contralateral sensorimotor mu (8–12 Hz) and beta (13–35 Hz) rhythms during release of each motor command. We report that motor commands were most often relea...