Deriving causal relationships in resting-state functional connectivity using SSFO-based optogenetic fMRI.

Objective.The brain network has been extensively studied as a collection of brain regions that are functionally inter-connected. However, the study of the causal relationship in brain-wide functional connectivity, which is critical to the brain function, remains challenging. We aim to examine the feasibility of using (SSFO)-based optogenetic functional magnetic resonance imaging to infer the causal relationship (i.e. directional information) in the brain network.Approach.We combined SSFO-based optogenetics with fMRI in a resting-state rodent model to study how a local increase of excitability affects brain-wide neural activity and resting-state functional connectivity (RSFC). We incorporated Pearson's correlation and partial correlation analyses in a graphic model to derive the directional information in connections exhibiting RSFC modulations.Main results. When the dentate gyrus (DG) was sensitized by SSFO activation, we found significantly changed activity and connectivity in several brain regions associated with the DG, particularly in the medial prefrontal cortex Our causal inference result shows an 84%-100% accuracy rate compared to the directional information based on anatomical tracing data.Significance.This study establishes a system to investigate the relationship between local region activity and RSFC modulation, and provides a way to analyze the underlying causal relationship between brain regions.

A Critical Role of Basolateral Amygdala-to-Nucleus Accumbens Projection in Sleep Regulation of Reward Seeking.

BACKGROUND: Sleep impacts reward-motivated behaviors partly by retuning the brain reward circuits. The nucleus accumbens (NAc) is a reward processing hub sensitive to acute sleep deprivation. Glutamatergic transmission carrying reward-associated signals converges in the NAc and regulates various aspects of reward-motivated behaviors. The basolateral amygdala projection (BLAp) innervates broad regions of the NAc and critically regulates reward seeking. METHODS: Using slice electrophysiology, we measured how acute sleep deprivation alters transmission at BLAp-NAc synapses in male C57BL/6 mice. Moreover, using SSFO (stabilized step function opsin) and DREADDs (designer receptors exclusively activated by designer drugs) (Gi) to amplify and reduce transmission, respectively, we tested behavioral consequences following bidirectional manipulations of BLAp-NAc transmission. RESULTS: Acute sleep deprivation increased sucrose self-administration in mice and altered the BLAp-NAc transmission in a topographically specific manner. It selectively reduced glutamate release at the rostral BLAp (rBLAp) onto ventral and lateral NAc (vlNAc) synapses, but spared caudal BLAp onto medial NAc synapses. Furthermore, experimentally facilitating glutamate release at rBLAp-vlNAc synapses suppressed sucrose reward seeking. Conversely, mimicking sleep deprivation-induced reduction of rBLAp-vlNAc transmission increased sucrose reward seeking. Finally, facilitating rBLAp-vlNAc transmission per se did not promote either approach motivation or aversion. CONCLUSIONS: Sleep acts on rBLAp-vINAc transmission gain control to regulate established reward seeking but does not convey approach motivation or aversion on its own.

Bidirectional Control of Generalized Epilepsy Networks via Rapid Real-Time Switching of Firing Mode.

Thalamic relay neurons have well-characterized dual firing modes: bursting and tonic spiking. Studies in brain slices have led to a model in which rhythmic synchronized spiking (phasic firing) in a population of relay neurons leads to hyper-synchronous oscillatory cortico-thalamo-cortical rhythms that result in absence seizures. This model suggests that blocking thalamocortical phasic firing would treat absence seizures. However, recent in vivo studies in anesthetized animals have questioned this simple model. Here we resolve this issue by developing a real-time, mode-switching approach to drive thalamocortical neurons into or out of a phasic firing mode in two freely behaving genetic rodent models of absence epilepsy. Toggling between phasic and tonic firing in thalamocortical neurons launched and aborted absence seizures, respectively. Thus, a synchronous thalamocortical phasic firing state is required for absence seizures, and switching to tonic firing rapidly halts absences. This approach should be useful for modulating other networks that have mode-dependent behaviors.

Prefrontal Cortex to Accumbens Projections in Sleep Regulation of Reward.

UNLABELLED: Sleep profoundly affects the emotional and motivational state. In humans and animals, loss of sleep often results in enhanced motivation for reward, which has direct implications for health risks as well as potential benefits. Current study aims at understanding the mechanisms underlying sleep deprivation (SDe)-induced enhancement of reward seeking. We found that after acute SDe, mice had an increase in sucrose seeking and consumption but not food intake, suggesting a selective enhancement of motivation for reward. In the nucleus accumbens (NAc), a key brain region regulating emotional and motivational responses, we observed a decrease in the ratio of the overall excitatory over inhibitory synaptic inputs onto NAc principle neurons after SDe. The shift was partly mediated by reduced glutamatergic transmission of presynaptic origin. Further analysis revealed that there was selective reduction of the glutamate release probability at the medial prefrontal cortex (mPFC)-to-NAc synapses, but not those from the hippocampus, thalamus, or the basal lateral amygdala. To reverse this SDe-induced synaptic alteration, we expressed the stabilized step function opsin (SSFO) in the mPFC; optogenetic stimulation of SSFO at mPFC-to-NAc projection terminals persistently enhanced the action potential-dependent glutamate release. Intra-NAc optogenetic stimulation of SSFO selectively at mPFC-to-NAc terminals restored normal sucrose seeking in mice after SDe without affecting food intake. These results highlight the mPFC-to-NAc projection as a key circuit-based target for sleep to regulate reward-motivated behaviors. SIGNIFICANCE STATEMENT: Sleep loss, a costly challenge of modern society, has profound physiological and psychological consequences, including altered reward processing of the brain. The current study aims at understanding the mechanisms underlying sleep deprivation-induced enhancement of reward seeking. We identify that the medial prefrontal cortex (mPFC)-to-nucleus accumbens (NAc) glutamatergic transmission is selectively weakened following acute sleep deprivation, whose restoration normalizes reward seeking in sleep-deprived mice. These results suggest a possibility of normalizing sleep deprivation-induced abnormal reward seeking by targeting specific neural projections, and they demonstrate the mPFC-to-NAc glutamatergic projection as a key circuit-based target for sleep to regulate reward-motivated behaviors.