Effective planning involves knowing where different actions take us. However, natural environments are rich and complex, leading to an exponential increase in memory demand as a plan grows in depth. One potential solution is to filter out features of the environment irrelevant to the task at hand. This enables a shared model of transition dynamics to be used for planning over a range of different input features. Here, we asked human participants (13 male, 16 female) to perform a sequential decision-making task, designed so that knowledge should be integrated independently of the input features (visual cues) present in one case but not in another. Participants efficiently switched between using a low-dimensional (cue independent) and a high-dimensional (cue specific) representation of state transitions. fMRI data identified the medial temporal lobe as a locus for learning state transitions. Within this region, multivariate patterns of BOLD responses were less correlated between trials with differing input f...

Motor skills learning is classically associated with brain regions including cerebral and cerebellar cortices and basal ganglia nuclei. Less is known about the role of the hippocampus in the acquisition and storage of motor skills. Here, we show that mice receiving a long-term training in the accelerating rotarod display marked hippocampal transcriptional changes and reduced pyramidal neurons activity in the CA1 region when compared with naive mice. Then, we use mice in which neural ensembles are permanently labeled in an Egr1 activity-dependent fashion. Using these mice, we identify a subpopulation of Egr1 -expressing pyramidal neurons in CA1 activated in short-term (STT) and long-term (LTT) trained mice in the rotarod task. When Egr1 is downregulated in the CA1 or these neuronal ensembles are depleted, motor learning is improved whereas their chemogenetic stimulation impairs motor learning performance. Thus, Egr1 organizes specific CA1 neuronal ensembles during the accelerating rotarod task that limit mo...

The mechanistic target of rapamycin (mTOR) signaling pathway plays a major role in key cellular processes including metabolism and differentiation; however, the role of mTOR in microglia and its importance in Alzheimer's disease (AD) have remained largely uncharacterized. We report that selective loss of Tsc1 , a negative regulator of mTOR, in microglia in mice of both sexes, caused mTOR activation and upregulation of Trem2 with enhanced β-Amyloid (Aβ) clearance, reduced spine loss, and improved cognitive function in the 5XFAD AD mouse model. Combined loss of Tsc1 and Trem2 in microglia led to reduced Aβ clearance and increased Aβ plaque burden revealing that Trem2 functions downstream of mTOR. Tsc1 mutant microglia showed increased phagocytosis with upregulation of CD68 and Lamp1 lysosomal proteins. In vitro studies using Tsc1 -deficient microglia revealed enhanced endocytosis of the lysosomal tracker indicator Green DND-26 suggesting increased lysosomal activity. Incubation of Tsc1 -deficient microglia w...

The imbalanced conditions of pronociceptive ON-cells and antinociceptive OFF-cells in the rostral ventromedial medulla (RVM) alter nociceptive transmission and play an important role in the development of chronic pain. This study aimed to explore the neuroplastic mechanisms of the RVM ON-cells and OFF-cells in a male rat model of experimental occlusal interference (EOI)-induced nociceptive behavior reflecting orofacial hyperalgesia and in modified models involving EOI removal at early and later stages. We recorded the mechanical head withdrawal thresholds, orofacial operant behaviors, and the activity of identified RVM ON-cells and OFF-cells in these rats. EOI-induced orofacial hyperalgesia could be relieved by EOI removal around postoperative day 3; this effect could be inhibited by intra-RVM microinjection of the κ-opioid receptor agonist U-69593. EOI removal around postoperative day 8 did not relieve the orofacial hyperalgesia, which could, however, be reversed by intra-RVM microinjection of the NK-1 (n...

Pain and emotion are strongly regulated by neurons in the central nucleus of the amygdala (CeA), a major output of the limbic system; yet, the neuronal signaling pathways underlying this modulation are incompletely understood. Here, we characterized a subpopulation of CeA neurons that express the CaMKIIα gene (CeACAM neurons) and project to the lateral parabrachial nucleus (LPBN), a brainstem region known for its critical role in distributing nociceptive and other aversive signals throughout the brain. In male Sprague Dawley rats, we show that CeACAM-LPBN neurons are GABAergic and mostly express somatostatin. In anaesthetized rats, optogenetic stimulation of CeACAM-LPBN projections inhibited responses of LPBN neurons evoked by electrical activation of Aδ- and C-fiber primary afferents; this inhibition could be blocked by intra-LPBN application of the GABAA receptor antagonist bicuculline. CeACAM-LPBN stimulation also dampened LPBN responses to noxious mechanical, thermal, and chemical stimuli. In behaving ...

Relational memory, the ability to make and remember associations between objects, is an essential component of mammalian reasoning. In relational memory tasks, it has been shown that periods of offline processing, such as sleep, are critical to making indirect associations. To understand biophysical mechanisms behind the role of sleep in improving relational memory, we developed a model of the thalamocortical network to test how slow-wave sleep affects performance on an unordered relational memory task. First, the model was trained in the awake state on a paired associate inference task, in which the model learned to recall direct associations. After a period of subsequent slow-wave sleep, the model developed the ability to recall indirect associations. We found that replay, during sleep, of memory patterns learned in awake increased synaptic connectivity between neurons representing the item that was overlapping between tasks and neurons representing the unlinked items of the different tasks; this forms a...

The lateral preoptic (LPO) hypothalamus is a center for NREM and REM sleep induction and NREM sleep homeostasis. Although LPO is needed for NREM sleep, we found that calcium signals were, surprisingly, highest in REM sleep. Furthermore, and equally surprising, NMDA receptors in LPO were the main drivers of excitation. Deleting the NMDA receptor GluN1 subunit from LPO abolished calcium signals in all cells and produced insomnia. Mice of both sexes had highly fragmented NREM sleep-wake patterns and could not generate conventionally classified REM sleep. The sleep phenotype produced by deleting NMDA receptors depended on where in the hypothalamus the receptors were deleted. Deleting receptors from the anterior hypothalamic area (AHA) did not influence sleep-wake states. The sleep fragmentation originated from NMDA receptors on GABA neurons in LPO. Sleep fragmentation could be transiently overcome with sleeping medication (zolpidem) or sedatives (dexmedetomidine; Dex). By contrast, fragmentation persisted unde...

Autism spectrum disorder (ASD) is a developmental disorder that is characterized by difficulties with social interaction and interpersonal communication. It has been argued that abnormal attentional function to exogenous stimuli precedes and contributes to the core ASD symptoms. Notably, the locus ceruleus (LC) and its noradrenergic projections throughout the brain modulate attentional function, but the extent to which this locus ceruleus–norepinephrine (LC–NE) system influences attention in individuals with ASD, who frequently exhibit dysregulated alerting and attention orienting, is unknown. We examined dynamic attention control in girls and boys with ASD at rest using the pupil dilation response (PDR) as a noninvasive measure of LC–NE activity. When gender- and age-matched neurotypical participants were passively exposed to an auditory stream, their PDR decreased for recurrent stimuli but remained sensitive to surprising deviant stimuli. In contrast, children with ASD showed less habituation to recurren...

Sensory evidence accumulation is considered a hallmark of decision-making in noisy environments. Integration of sensory inputs has been traditionally studied using passive stimuli, segregating perception from action. Lessons learned from this approach, however, may not generalize to ethological behaviors like navigation, where there is an active interplay between perception and action. We designed a sensory-based sequential decision task in virtual reality in which humans and monkeys navigated to a memorized location by integrating optic flow generated by their own joystick movements. A major challenge in such closed-loop tasks is that subjects' actions will determine future sensory input, causing ambiguity about whether they rely on sensory input rather than expectations based solely on a learned model of the dynamics. To test whether subjects integrated optic flow over time, we used three independent experimental manipulations, unpredictable optic flow perturbations, which pushed subjects off their traje...