Anatomically Defined and Functionally Distinct Dorsal Raphe Serotonin Sub-systems.

The dorsal raphe (DR) constitutes a major serotonergic input to the forebrain and modulates diverse functions and brain states, including mood, anxiety, and sensory and motor functions. Most functional studies to date have treated DR serotonin neurons as a single population. Using viral-genetic methods, we found that subcortical- and cortical-projecting serotonin neurons have distinct cell-body distributions within the DR and differentially co-express a vesicular glutamate transporter. Further, amygdala- and frontal-cortex-projecting DR serotonin neurons have largely complementary whole-brain collateralization patterns, receive biased inputs from presynaptic partners, and exhibit opposite responses to aversive stimuli. Gain- and loss-of-function experiments suggest that amygdala-projecting DR serotonin neurons promote anxiety-like behavior, whereas frontal-cortex-projecting neurons promote active coping in the face of challenge. These results provide compelling evidence that the DR serotonin system contains parallel sub-systems that differ in input and output connectivity, physiological response properties, and behavioral functions.

Complementary Functional Organization of Neuronal Activity Patterns in the Perirhinal, Lateral Entorhinal, and Medial Entorhinal Cortices.

It is commonly conceived that the cortical areas of the hippocampal region are functionally divided into the perirhinal cortex (PRC) and the lateral entorhinal cortex (LEC), which selectively process object information; and the medial entorhinal cortex (MEC), which selectively processes spatial information. Contrary to this notion, in rats performing a task that demands both object and spatial information processing, single neurons in PRC, LEC, and MEC, including those in both superficial and deep cortical areas and in grid, border, and head direction cells of MEC, have a highly similar range of selectivity to object and spatial dimensions of the task. By contrast, representational similarity analysis of population activity reveals a key distinction in the organization of information in these areas, such that PRC and LEC populations prioritize object over location information, whereas MEC populations prioritize location over object information. These findings bring to the hippocampal system a growing emphasis on population analyses as a powerful tool for characterizing neural representations supporting cognition and memory. SIGNIFICANCE STATEMENT: Contrary to the common view that brain regions in the "what" and "where" streams distinctly process object and spatial cues, respectively, we found that both streams encode both object and spatial information but distinctly organize memories for objects and space. Specifically, perirhinal cortex and lateral entorhinal cortex represent objects and, within the object-specific representations, the locations where they occur. Conversely, medial entorhinal cortex represents relevant locations and, within those spatial representations, the objects that occupy them. Furthermore, these findings reach beyond simple notions of perirhinal cortex and lateral entorhinal cortex neurons as object detectors and MEC neurons as position detectors, and point to a more complex organization of memory representations within the medial temporal lobe system.

Paradoxical increases in anterior cingulate cortex activity during nitrous oxide-induced analgesia reveal a signature of pain affect.

The general consensus is that increases in neuronal activity in the anterior cingulate cortex (ACC) contribute to pain's negative affect. Here, using in vivo imaging of neuronal calcium dynamics in mice, we report that nitrous oxide, a general anesthetic that reduces pain affect, paradoxically, increases ACC spontaneous activity. As expected, a noxious stimulus also increased ACC activity. However, as nitrous oxide increases baseline activity, the relative change in activity from pre-stimulus baseline was significantly less than the change in the absence of the general anesthetic. We suggest that this relative change in activity represents a neural signature of the affective pain experience. Furthermore, this signature of pain persists under general anesthesia induced by isoflurane, at concentrations in which the mouse is unresponsive. We suggest that this signature underlies the phenomenon of connected consciousness, in which use of the isolated forelimb technique revealed that pain percepts can persist in anesthetized patients.

Temporal evolution of cortical ensembles promoting remote memory retrieval.

Memories of fearful events can last a lifetime. The prelimbic (PL) cortex, a subregion of prefrontal cortex, plays a critical role in fear memory retrieval over time. Most studies have focused on acquisition, consolidation, and retrieval of recent memories, but much less is known about the neural mechanisms of remote memory. Using a new knock-in mouse for activity-dependent genetic labeling (TRAP2), we demonstrate that neuronal ensembles in the PL cortex are dynamic. PL neurons TRAPed during later memory retrievals are more likely to be reactivated and make larger behavioral contributions to remote memory retrieval compared to those TRAPed during learning or early memory retrieval. PL activity during learning is required to initiate this time-dependent reorganization in PL ensembles underlying memory retrieval. Finally, while neurons TRAPed during earlier and later retrievals have similar broad projections throughout the brain, PL neurons TRAPed later have a stronger functional recruitment of cortical targets.

Thirst-associated preoptic neurons encode an aversive motivational drive.

Water deprivation produces a drive to seek and consume water. How neural activity creates this motivation remains poorly understood. We used activity-dependent genetic labeling to characterize neurons activated by water deprivation in the hypothalamic median preoptic nucleus (MnPO). Single-cell transcriptional profiling revealed that dehydration-activated MnPO neurons consist of a single excitatory cell type. After optogenetic activation of these neurons, mice drank water and performed an operant lever-pressing task for water reward with rates that scaled with stimulation frequency. This stimulation was aversive, and instrumentally pausing stimulation could reinforce lever-pressing. Activity of these neurons gradually decreased over the course of an operant session. Thus, the activity of dehydration-activated MnPO neurons establishes a scalable, persistent, and aversive internal state that dynamically controls thirst-motivated behavior.