In vivo calcium imaging through microendoscopic lenses enables imaging of previously inaccessible neuronal populations deep within the brains of freely moving animals. However, it is computationally challenging to extract single-neuronal activity from microendoscopic data, because of the very large background fluctuations and high spatial overlaps intrinsic to this recording modality. Here, we describe a new constrained matrix factorization approach to accurately separate the background and then demix and denoise the neuronal signals of interest. We compared the proposed method against previous independent components analysis and constrained nonnegative matrix factorization approaches. On both simulated and experimental data recorded from mice, our method substantially improved the quality of extracted cellular signals and detected more well-isolated neural signals, especially in noisy data regimes. These advances can in turn significantly enhance the statistical power of downstream analyses, and ultimately improve scientific conclusions derived from microendoscopic data.

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Highlights d PVT-NAc neurons develop inhibitory responses to rewardpredictive cues d Glutamatergic PFC axons to PVT show reductions in activity to cues d GABAergic LHA axons to PVT show increases in activity during licking d Optogenetic stimulation of PFC axons disrupts PVT-NAc cue encoding and behavior

BACKGROUND Understanding the neural mechanisms of psychiatric disorders requires the use of rodent models; however, frontal-striatal homologies between rodents and primates are unclear. In contrast, within the striatum, the shell of the nucleus accumbens, the hippocampal projection zone, and the amygdala projection zone (referred to as the striatal emotion processing network, EPN) are conserved across species. We used the relationship between the EPN and projections from the anterior cingulate and orbitofrontal cortices (ACC/OFC) to assess network similarities across rats and monkeys. METHODS We first compared the location and extent of each major component of the EPN in rats and macaques. Next, we used anatomical cases with anterograde injections in ACC/OFC to determine the extent to which cortico-striatal terminal fields overlapped with these components, and with each other. RESULTS The location and size of each component of the EPN were similar across species, containing projections primarily from infralimbic cortex (IL) in rats and area 25 (a25) in monkeys. Other ACC/OFC terminals overlapped extensively with IL/a25 projections, supporting cross-species similarities between medial versus lateral OFC. However, dorsal ACC had different connectivity profiles across species. These results were used to segment the monkey and rat striata according to ACC/OFC inputs. CONCLUSIONS Based on connectivity with the EPN, and consistent with prior literature, IL and a25 are likely homologues. We also see evidence of homologies across medial versus lateral OFC. Along with segmenting the striatum and identifying striatal hubs of overlapping inputs, these results help to translate findings between rodent models and human pathology.

Medial prefrontal cortical areas have been hypothesized to underlie altered contextual processing in posttraumatic stress disorder (PTSD). We investigated brain signaling of contextual information in this disorder. Eighteen PTSD subjects and 16 healthy trauma-exposed subjects underwent a two-day fear conditioning and extinction paradigm. On day 1, within visual context A, a conditioned stimulus (CS) was followed 60% of the time by an electric shock (conditioning). The conditioned response was then extinguished (extinction learning) in context B. On day 2, recall of the extinction memory was tested in context B. Skin conductance response (SCR) and functional magnetic resonance imaging (fMRI) data were collected during context presentations. There were no SCR group differences in any context presentation. Concerning fMRI data, during late conditioning, when context A signaled danger, PTSD subjects showed dorsal anterior cingulate cortical (dACC) hyperactivation. During early extinction, when context B had not yet fully acquired signal value for safety, PTSD subjects still showed dACC hyperactivation. During late extinction, when context B had come to signal safety, they showed ventromedial prefrontal cortex (vmPFC) hypoactivation. During early extinction recall, when context B signaled safety, they showed both vmPFC hypoactivation and dACC hyperactivation. These findings suggest that PTSD subjects show alterations in the processing of contextual information related to danger and safety. This impairment is manifest even prior to a physiologically-measured, cue-elicited fear response, and characterized by hypoactivation in vmPFC and hyperactivation in dACC.

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD.prefrontal cortex | anxiety disorders | posttraumatic stress disorder | phosphorylated extracellular signal-regulated kinase | accumbens D eep brain stimulation (DBS) is a neurosurgical technique that has become the standard of care for movement disorders (1-3) and is under investigation in major depression (4-6). In DBS, chronic high-frequency stimulation of specific sites reduces symptoms in medically intractable illness. DBS of the ventral capsule and the adjacent ventral striatum (VC/VS) has been used to treat refractory obsessive-compulsive disorder (OCD) in the European Union and the United States (7-10). Little is known about how DBS acts in OCD, emphasizing the need for translational animal studies. A prominent feature observed in most OCD patients is repetitive avoidance behaviors to perceived threats (11,12). The persistent avoidance in OCD suggests a deficit in circuits that regulate fear extinction (11). Given the strong parallels between fear circuits in rodents and humans (13), well-characterized rodent models of fear conditioning could shed light on DBS mechanisms in OCD and related illnesses that feature pathological anxiety.The DBS target for OCD is the VC/VS (14), which contains fiber bundles interconnecting cortical areas implicated in fear extinction, such as the ventromedial prefrontal cortex, the dorsal anterior cingulate cortex, and the orbitofrontal cortex (OFC), with subcortical areas implicated in conditioned fear, such as the amygdala (15). Previous studies in anesthetized rats (16,17) have shown that DBS of the VS modifies the excitability of the OFC as well as prelimbic (PL) and infralimbic (IL) prefron...

The habenula is a tiny brain region the size of a pea in humans. This region is highly conserved across vertebrates and has been traditionally overlooked by neuroscientists. The name habenula is derived from the Latin word habena, meaning "little rein", because of its elongated shape. Originally its function was thought to be related to the regulation of the nearby pineal gland (which Rene Descartes described as the "principal seat of the soul"). More recent evidence, however, demonstrates that the habenula acts as a critical neuroanatomical hub that connects and regulates brain regions important for divergent motivational states and cognition. In this Primer, we will discuss the recent and converging evidence that points to the habenula as a key brain region for motivation and decision-making.

Background-Previous work has implicated noradrenergic beta-receptors in the consolidation and reconsolidation of conditioned fear. Less is known, however, about their role in fear expression and extinction. The beta-receptor blocker propranolol has been used clinically to reduce anxiety. Using an auditory fear conditioning task in rats, we assessed the effects of propranolol on the expression and extinction of two measures of conditioned fear: freezing and suppression of bar pressing.