Local sleep and mental fatigue - Local sleep and mental fatigue PROJECT SUMMARY Mental fatigue—a feeling of exhaustion often accompanied by the sense that every task requires great effort—is prevalent in neurological and psychiatric diseases. In healthy subjects, it is a common symptom ensuing after intense learning or sleep deprivation. Mental fatigue is also frequent when sleep is poor and can be relieved by improving sleep quality. Moreover, the broad cognitive impairment that accompanies mental fatigue is resolved by sleeping but not by resting while awake. Despite the evidence linking mental fatigue with brain dysfunctions and sleep deficits, the reasons why the brain gets “tired” remain unknown. This proposal tests a novel, circuit-level hypothesis about the neural mechanisms of mental fatigue caused by sleep loss or intense learning. In these cases, we hypothesize that a key underlying mechanism is the increasing occurrence, within corticothalamic networks, of local neuronal OFF periods in wake, triggered by the activation of Martinotti cells (MaCs). In NIH-funded groundwork that led to this hypothesis we demonstrated, in both rodents and humans, that sleep deprivation leads to “local sleep” in wake: even though the rest of the brain is awake, local groups of cortical neurons briefly stop firing (OFF periods), as they usually only do, in a widespread manner, during sleep slow waves. Even though subjects are behaviorally awake, if “local sleep” occurs in cortical areas involved in task execution, performance is impaired. In further work, we demonstrated that the widespread OFF periods underlying the slow waves of sleep are promoted by the activation of MaCs, which are somatostatin-positive (SOM+) GABAergic neurons found throughout cortex. Once recruited by strong excitatory inputs from pyramidal neurons, MaCs can act as master regulators of cortical excitability by inhibiting all other cell types. Finally, we found that extended wake and intense learning lead to increased neuronal excitability due to the progressive strengthening of cortical glutamatergic connections, which are renormalized (weakened) by sleep and not simply by rest. Guided by these findings and preliminary data, we propose that a key mechanism underlying mental fatigue is the increased excitability of MaCs and their maladaptive triggering of OFF periods during wake. To test this hypothesis, we will perform high-density Neuropixels recordings in mice and rats in multiple cortical and subcortical areas. These recordings will be combined with optogenetic tagging to determine, first, whether extended wake or intense learning will activate MaCs and trigger local OFF periods in wake. Guided by a new large-scale sleep/wake model of corticothalamic circuits, we will then test two key predictions in vivo. Using opto/chemogenetics, we will determine whether, after extended wake or intense learning, local OFF periods in wake are prevented by silencing MaCs and, conversely, whether they are triggered by the activation of MaCs even in fully rested animals. If successful, we will uncover: 1) a candidate circuit mediating mental fatigue after extended wake and intense learning; 2) a key mechanism through which fatigue is mediated—the induction of OFF periods in corticothalamic networks due to the progressive build-up of synaptic strength in wake. Exploratory analysis of unit data collected in thalamic, striatal, and hippocampal areas will also determine whether local sleep extends subcortically, potentially contributing to the impairment in performance and motivation associated with mental fatigue.
