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.
ABSTRACT 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 cortex (ACC) and orbitofrontal cortex (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 anatomic cases with anterograde injections in ACC/OFC to determine the extent to which corticostriatal 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 in rats and area 25 in monkeys. Other ACC/OFC terminals overlapped extensively with infralimbic cortex/area 25 projections, supporting cross-species similarities in OFC topography. 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, the infralimbic cortex and area 25 are likely homologues. We also see evidence of OFC homologies. Along with segmenting the striatum and identifying striatal hubs of overlapping inputs, these results help to translate findings between rodent models and human pathology.
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.
Abstract Background Recent research in humans and rodents has explored the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) as a possible treatment for drug ...addiction. However, the optimum electrode placement and optimum DBS parameters have not been thoroughly studied. Here we varied stimulation sites and frequencies to determine if DBS of the VS could facilitate the extinction of morphine conditioned place preference (CPP) in rats. Methods Rats were implanted with DBS electrodes in the dorsal or ventral subregions of the VS and trained to the morphine-CPP. Subsequently, rats received extinction sessions over 9 days, combined with 60 min of either high (130 Hz) or low (20 Hz) frequency DBS. To study circuit-wide activations after DBS of the VS, c-fos immunohistochemistry was performed in regions involved in the extinction of drug seeking behaviors. Results High frequency DBS of the dorsal-VS impaired both extinction training and extinction memory, whereas high frequency DBS of the ventral-VS had no effect. In contrast, low frequency DBS of the dorsal-VS strengthened extinction memory when tested 2 or 9 days after the cessation of stimulation. Both DBS frequencies increased c-fos expression in the infralimbic prefrontal cortex, but only low frequency DBS increased c-fos expression in the basal amygdala and the medial portion of the central amygdala. Conclusions Our results suggest that low frequency (rather than high frequency) DBS of the dorsal-VS strengthens extinction memory and may be a potential adjunct for extinction-based therapies for treatment-refractory opioid addicts.
Oxytocin (OT) is critical for the expression of social behavior across a wide array of species; however, the role of this system in the encoding of socially relevant information is not well ...understood. In the present study, we show that chemogenetic activation of OT neurons within the paraventricular nucleus of the hypothalamus (PVH) of male mice (OT-Ires-Cre) enhanced social investigation during a social choice test, while chemogenetic inhibition of these neurons abolished typical social preferences. These data suggest that activation of the OT system is necessary to direct behavior preferentially toward social stimuli. To determine whether the presence of a social stimulus is sufficient to induce activation of PVH-OT neurons, we performed the first definitive recording of OT neurons in awake mice using two-photon calcium imaging. These recordings demonstrate that social stimuli activate PVH-OT neurons and that these neurons differentially encode social and nonsocial stimuli, suggesting that PVH-OT neurons may act to convey social salience of environmental stimuli. Finally, an attenuation of social salience is associated with social disorders, such as autism. We therefore also examined possible OT system dysfunction in a mouse model of autism,
knock-out (KO) mice. Male
KO mice showed a marked reduction in PVH-OT neuron number and administration of an OT receptor agonist improved social deficits. Overall, these data suggest that the presence of a social stimulus induces activation of the PVH-OT neurons to promote adaptive social behavior responses.
Although the oxytocin (OT) system is well known to regulate a diverse array of social behaviors, the mechanism in which OT acts to promote the appropriate social response is poorly understood. One hypothesis is that the presence of social conspecifics activates the OT system to generate an adaptive social response. Here, we selectively recorded from OT neurons in the paraventricular hypothalamic nucleus (PVH) to show that social stimulus exposure indeed induces activation of the OT system. We also show that activation of the OT system is necessary to promote social behavior and that mice with abnormal social behavior have reduced numbers of PVH-OT neurons. Finally, aberrant social behavior in these mice was rescued by administration of an OT receptor agonist.
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.
Genetically encoded calcium indicators and optogenetics have revolutionized neuroscience by enabling the detection and modulation of neural activity with single-cell precision using light. To fully ...leverage the immense potential of these techniques, advanced optical instruments that can place a light on custom ensembles of neurons with a high level of spatial and temporal precision are required. Modern light sculpting techniques that have the capacity to shape a beam of light are preferred because they can precisely target multiple neurons simultaneously and modulate the activity of large ensembles of individual neurons at rates that match natural neuronal dynamics. The most versatile approach, computer-generated holography (CGH), relies on a computer-controlled light modulator placed in the path of a coherent laser beam to synthesize custom three-dimensional (3D) illumination patterns and illuminate neural ensembles on demand. Here, we review recent progress in the development and implementation of fast and spatiotemporally precise CGH techniques that sculpt light in 3D to optically interrogate neural circuit functions.
Much is known about the neural circuits of conditioned fear and its relevance to understanding anxiety disorders, but less is known about other anxiety-related behaviors such as active avoidance. ...Using a tone-signaled, platform-mediated avoidance task, we observed that pharmacological inactivation of the prelimbic prefrontal cortex (PL) delayed avoidance. Surprisingly, optogenetic silencing of PL glutamatergic neurons did not delay avoidance. Consistent with this, inhibitory but not excitatory responses of rostral PL neurons were associated with avoidance training. To test the importance of these inhibitory responses, we optogenetically stimulated PL neurons to counteract the tone-elicited reduction in firing rate. Photoactivation of rostral (but not caudal) PL neurons at 4 Hz impaired avoidance. These findings suggest that inhibitory responses of rostral PL neurons signal the avoidability of a potential threat and underscore the importance of designing behavioral optogenetic studies based on neuronal firing responses.
Motivational states consist of cognitive, emotional, and physiological components controlled by multiple brain regions. An integral component of this neural circuitry is the bed nucleus of the stria ...terminalis (BNST). Here, we identify that neurons within BNST that express the gene prepronociceptin (PnocBNST) modulate rapid changes in physiological arousal that occur upon exposure to motivationally salient stimuli. Using in vivo two-photon calcium imaging, we find that PnocBNST neuronal responses directly correspond with rapid increases in pupillary size when mice are exposed to aversive and rewarding odors. Furthermore, optogenetic activation of these neurons increases pupillary size and anxiety-like behaviors but does not induce approach, avoidance, or locomotion. These findings suggest that excitatory responses in PnocBNST neurons encode rapid arousal responses that modulate anxiety states. Further histological, electrophysiological, and single-cell RNA sequencing data reveal that PnocBNST neurons are composed of genetically and anatomically identifiable subpopulations that may differentially tune rapid arousal responses to motivational stimuli.
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•Prepronociceptin (Pnoc) defines a subpopulation of GABAergic neurons within BNST•PnocBNST neurons encode rapid changes in arousal to motivationally salient stimuli•Activation of PnocBNST neurons drives arousal responses and anxiety-like behavior•PnocBNST neurons exhibit diversity in both anatomical connectivity and genetic identity
Rodriguez-Romaguera et al. find an ensemble of neurons within the extended amygdala (BNST) that expresses the prepronociceptin gene and functions to encode the rapid arousal responses that are triggered by motivational stimuli.
The habenula Namboodiri, Vijay Mohan K.; Rodriguez-Romaguera, Jose; Stuber, Garret D.
CB/Current biology,
10/2016, Letnik:
26, Številka:
19
Journal Article
Recenzirano
Odprti dostop
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.
In this primer, Namboodiri et al. provide an introduction to the habenula, a brain region involved in regulating motivation and decision making. We focus on the various behavioral functions attributed to this neuroanatomical hub in the context of its input and output circuitry.
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