Anosognosia in hoarding disorder is predicted by alterations in cognitive and inhibitory control.

Insight impairment contributes significantly to morbidity in psychiatric disorders. The neurologic concept of anosognosia, reflecting deficits in metacognitive awareness of illness, is increasingly understood as relevant to psychopathology, but has been little explored in psychiatric disorders other than schizophrenia. We explored anosognosia as an aspect of insight impairment in n = 71 individuals with DSM-5 hoarding disorder. We used a standardized clutter severity measure to assess whether individuals with hoarding disorder underreport home clutter levels relative to independent examiners. We then explored whether underreporting, as a proxy for anosognosia, is predicted by clinical or neurocognitive behavioral measures. We found that individuals with hoarding disorder underreport their clutter, and that underreporting is predicted by objective severity of clutter. In an n = 53 subset of participants, we found that underreporting is predicted by altered performance on tests of cognitive control and inhibition, specifically Go/No-Go and Stroop tests. The relation of underreporting to objective clutter, the cardinal symptom of hoarding disorder, suggests that anosognosia may reflect core pathophysiology of the disorder. The neurocognitive predictors of clutter underreporting suggest that anosognosia in hoarding disorder shares a neural basis with metacognitive awareness deficits in other neuropsychiatric disorders and that executive anosognosia may be a transdiagnostic manifestation of psychopathology.

Valence processing alterations in SAPAP3 knockout mice and human OCD.

Abnormalities in valence processing - the processing of aversive or appetitive stimuli - may be an underrecognized component of obsessive-compulsive disorder (OCD). Preclinical rodent models have been critical in furthering pathophysiological understanding of OCD, yet there is a dearth of investigations examining whether rodent models of compulsive behavior show alterations in valence systems congruent with those seen in individuals with OCD. In this study, we sought to assess valence processing in a preclinical rodent model of compulsive behavior, the SAPAP3 knockout (KO) mouse model, and compare our preclinical findings to similar behavioral phenomena in OCD patients. In SAPAP3 KO mice, we used auditory fear conditioning and extinction to examine alterations in negative valence processing and reward-based operant conditioning to examine alterations in positive valence processing. We find that SAPAP3 KO mice show evidence of heightened negative valence processing through enhanced fear learning and impaired fear extinction. SAPAP3 KO mice also show deficits in reward acquisition and goal-directed behavior, suggesting impaired positive valence processing. In OCD patients, we used validated behavioral tests to assess explicit and implicit processing of fear-related facial expressions (negative valence) and socially-rewarding happy expressions (positive valence). We find similar trends towards enhanced negative and impaired positive valence processing in OCD patients. Overall, our results reveal valence processing abnormalities in a preclinical rodent model of compulsive behavior similar to those seen in OCD patients, with implications for valence processing alterations as novel therapeutic targets across a translational research spectrum.

Divergent encoding of active avoidance behavior in corticostriatal and corticolimbic projections.

Active avoidance behavior, in which an animal performs an action to avoid a stressor, is crucial for survival and may provide insight into avoidance behaviors seen in anxiety disorders. Active avoidance requires the dorsomedial prefrontal cortex (dmPFC), which is thought to regulate avoidance via downstream projections to the striatum and amygdala. However, the endogenous activity of dmPFC projections during active avoidance learning has never been recorded. Here we utilized fiber photometry to record from the dmPFC and its axonal projections to the dorsomedial striatum (DMS) and the basolateral amygdala (BLA) during active avoidance learning in both male and female mice. We examined neural activity during conditioned stimulus (CS) presentations and during clinically relevant behaviors such as active avoidance or cued freezing. Both prefrontal projections showed learning-related increases in activity during CS onset throughout active avoidance training. The dmPFC as a whole showed increased and decreased patterns of activity during avoidance and cued freezing, respectively. Finally, dmPFC-DMS and dmPFC-BLA projections show divergent encoding of active avoidance behavior, with the dmPFC-DMS projection showing increased activity and the dmPFC-BLA projection showing decreased activity during active avoidance. Our results demonstrate task-relevant encoding of active avoidance in projection-specific dmPFC subpopulations that play distinct but complementary roles in active avoidance learning.

Leveraging the Strengths of Psychologists With Lived Experience of Psychopathology.

Psychopathology is a common element of the human experience, and psychological scientists are not immune. Recent empirical data demonstrate that a significant proportion of clinical, counseling, and school psychology faculty and graduate students have lived experience, both past and present, of psychopathology. This commentary compliments these findings by leveraging the perspectives of the authors and signatories, who have personal lived experience of psychopathology, to improve professional inclusivity in these fields. By "coming out proud," the authors aim to foster discussion, research, and inclusion efforts as they relate to psychopathology experiences in psychological science. To that end, the authors describe considerations related to disclosure of lived experience, identify barriers to inclusion, and provide concrete recommendations for personal and systemic changes to improve recognition and acceptance of psychopathology lived experience among psychologists.

Measuring maladaptive avoidance: from animal models to clinical anxiety.

Avoiding stimuli that predict danger is required for survival. However, avoidance can become maladaptive in individuals who overestimate threat and thus avoid safe situations as well as dangerous ones. Excessive avoidance is a core feature of anxiety disorders, post-traumatic stress disorder (PTSD), and obsessive-compulsive disorder (OCD). This avoidance prevents patients from confronting maladaptive threat beliefs, thereby maintaining disordered anxiety. Avoidance is associated with high levels of psychosocial impairment yet is poorly understood at a mechanistic level. Many objective laboratory assessments of avoidance measure adaptive avoidance, in which an individual learns to successfully avoid a truly noxious stimulus. However, anxiety disorders are characterized by maladaptive avoidance, for which there are fewer objective laboratory measures. We posit that maladaptive avoidance behavior depends on a combination of three altered neurobehavioral processes: (1) threat appraisal, (2) habitual avoidance, and (3) trait avoidance tendency. This heterogeneity in underlying processes presents challenges to the objective measurement of maladaptive avoidance behavior. Here we first review existing paradigms for measuring avoidance behavior and its underlying neural mechanisms in both human and animal models, and identify how existing paradigms relate to these neurobehavioral processes. We then propose a new framework to improve the translational understanding of maladaptive avoidance behavior by adapting paradigms to better differentiate underlying processes and mechanisms and applying these paradigms in clinical populations across diagnoses with the goal of developing novel interventions to engage specific identified neurobehavioral targets.

Ketamine increases activity of a fronto-striatal projection that regulates compulsive behavior in SAPAP3 knockout mice.

Obsessive-Compulsive Disorder (OCD), characterized by intrusive thoughts (obsessions) and repetitive behaviors (compulsions), is associated with dysfunction in fronto-striatal circuits. There are currently no fast-acting pharmacological treatments for OCD. However, recent clinical studies demonstrated that an intravenous infusion of ketamine rapidly reduces OCD symptoms. To probe mechanisms underlying ketamine's therapeutic effect on OCD-like behaviors, we used the SAPAP3 knockout (KO) mouse model of compulsive grooming. Here we recapitulate the fast-acting therapeutic effect of ketamine on compulsive behavior, and show that ketamine increases activity of dorsomedial prefrontal neurons projecting to the dorsomedial striatum in KO mice. Optogenetically mimicking this increase in fronto-striatal activity reduced compulsive grooming behavior in KO mice. Conversely, inhibiting this circuit in wild-type mice increased grooming. Finally, we demonstrate that ketamine blocks the exacerbation of grooming in KO mice caused by optogenetically inhibiting fronto-striatal activity. These studies demonstrate that ketamine increases activity in a fronto-striatal circuit that causally controls compulsive grooming behavior, suggesting this circuit may be important for ketamine's therapeutic effects in OCD.

Frontostriatal Projections Regulate Innate Avoidance Behavior.

The dorsomedial prefrontal cortex (dmPFC) has been linked to avoidance and decision-making under conflict, key neural computations altered in anxiety disorders. However, the heterogeneity of prefrontal projections has obscured identification of specific top-down projections involved. While the dmPFC-amygdala circuit has long been implicated in controlling reflexive fear responses, recent work suggests that dmPFC-dorsomedial striatum (DMS) projections may be more important for regulating avoidance. Using fiber photometry recordings in both male and female mice during the elevated zero maze task, we show heightened neural activity in frontostriatal but not frontoamygdalar projection neurons during exploration of the anxiogenic open arms. Additionally, using optogenetics, we demonstrate that this frontostriatal projection preferentially excites postsynaptic D1 receptor-expressing neurons in the DMS and causally controls innate avoidance behavior. These results support a model for prefrontal control of defensive behavior in which the dmPFC-amygdala projection controls reflexive fear behavior and the dmPFC-striatum projection controls anxious avoidance behavior.SIGNIFICANCE STATEMENT The medial prefrontal cortex has been extensively linked to several behavioral symptom domains related to anxiety disorders, with much of the work centered around reflexive fear responses. Comparatively little is known at the mechanistic level about anxious avoidance behavior, a core feature across anxiety disorders. Recent work has suggested that the striatum may be an important hub for regulating avoidance behaviors. Our work uses optical circuit dissection techniques to identify a specific corticostriatal circuit involved in encoding and controlling avoidance behavior. Identifying neural circuits for avoidance will enable the development of more targeted symptom-specific treatments for anxiety disorders.

Software-Based Phase Control, Video-Rate Imaging, and Real-Time Mosaicing With a Lissajous-Scanned Confocal Microscope.

We present software-based methods for automatic phase control and for mosaicing high-speed, Lissajous-scanned images. To achieve imaging speeds fast enough for mosaicing, we first increase the image update rate tenfold from 3 to 30 Hz, then vertically interpolate each sparse image in real-time to eliminate fixed pattern noise. We validate our methods by imaging fluorescent beads and automatically maintaining phase control over the course of one hour. We then image fixed mouse brain tissues at varying update rates and compare the resulting mosaics. Using reconstructed image data as feedback for phase control eliminates the need for phase sensors and feedback controllers, enabling long-term imaging experiments without additional hardware. Mosaicing subsampled images results in video-rate imaging speeds, nearly fully recovered spatial resolution, and millimeter-scale fields of view.

Cortico-Basal Ganglia Circuit Function in Psychiatric Disease.

Circuit dysfunction models of psychiatric disease posit that pathological behavior results from abnormal patterns of electrical activity in specific cells and circuits in the brain. Many psychiatric disorders are associated with abnormal activity in the prefrontal cortex and in the basal ganglia, a set of subcortical nuclei implicated in cognitive and motor control. Here we discuss the role of the basal ganglia and connected prefrontal regions in the etiology and treatment of obsessive-compulsive disorder, anxiety, and depression, emphasizing mechanistic work in rodent behavioral models to dissect causal cortico-basal ganglia circuits underlying discrete behavioral symptom domains relevant to these complex disorders.

Basomedial amygdala mediates top-down control of anxiety and fear.

Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.

Mapping Anatomy to Behavior in Thy1:18 ChR2-YFP Transgenic Mice Using Optogenetics.

Linking the activity of defined neural populations with behavior is a key goal of neuroscience. In the context of controlling behavior, electrical stimulation affords researchers precision in the temporal domain with gross regional specificity, whereas pharmacology allows for more specific manipulation of cell types, but in the absence of temporal precision. The use of microbial opsins--light activated, genetically encoded ion channels and pumps--to control mammalian neurons now allows researchers to "sensitize" genetically and/or topologically defined populations of neurons to light to induce either depolarization or hyperpolarization in both a cell-type-specific and temporally precise manner not achievable with previous techniques. Here, we describe the use of transgenic mice expressing the blue-light gated cation channel Channelrhodopsin-2 (ChR2) under control of the Thy1 promoter for the purpose of linking neuronal activity to behavior through restricted delivery of light to an anatomic region of interest. The surgical procedure for implanting a fiber-optic light delivery guide into the mouse brain, the process of optically stimulating the brain in a behaving animal, and post hoc evaluation are given, along with necessary reagents and discussion of common technical problems and their solutions.

Natural neural projection dynamics underlying social behavior.

Social interaction is a complex behavior essential for many species and is impaired in major neuropsychiatric disorders. Pharmacological studies have implicated certain neurotransmitter systems in social behavior, but circuit-level understanding of endogenous neural activity during social interaction is lacking. We therefore developed and applied a new methodology, termed fiber photometry, to optically record natural neural activity in genetically and connectivity-defined projections to elucidate the real-time role of specified pathways in mammalian behavior. Fiber photometry revealed that activity dynamics of a ventral tegmental area (VTA)-to-nucleus accumbens (NAc) projection could encode and predict key features of social, but not novel object, interaction. Consistent with this observation, optogenetic control of cells specifically contributing to this projection was sufficient to modulate social behavior, which was mediated by type 1 dopamine receptor signaling downstream in the NAc. Direct observation of deep projection-specific activity in this way captures a fundamental and previously inaccessible dimension of mammalian circuit dynamics.

Dopaminergic Dynamics Contributing to Social Behavior.

Social interaction is a complex behavior that is essential for the survival of many species, and it is impaired in a broad range of neuropsychiatric disorders. Several cortical and subcortical brain regions have been implicated in a variety of sociosexual behaviors, with pharmacological studies pointing to a key role of the neurotransmitter dopamine. However, little is understood about the real-time circuit dynamics causally underlying social interaction. Here, we consider current knowledge on the role of brain reward circuitry in same-sex social behavior and describe findings from new methods for probing how this circuitry governs social motivation in health and disease.

Dopamine neurons modulate neural encoding and expression of depression-related behaviour.

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia. Dopamine neurons involved in reward and motivation are among many neural populations that have been hypothesized to be relevant, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.

Optetrode: a multichannel readout for optogenetic control in freely moving mice.

Recent advances in optogenetics have improved the precision with which defined circuit elements can be controlled optically in freely moving mammals; in particular, recombinase-dependent opsin viruses, used with a growing pool of transgenic mice expressing recombinases, allow manipulation of specific cell types. However, although optogenetic control has allowed neural circuits to be manipulated in increasingly powerful ways, combining optogenetic stimulation with simultaneous multichannel electrophysiological readout of isolated units in freely moving mice remains a challenge. We designed and validated the optetrode, a device that allows for colocalized multi-tetrode electrophysiological recording and optical stimulation in freely moving mice. Optetrode manufacture employs a unique optical fiber-centric coaxial design approach that yields a lightweight (2 g), compact and robust device that is suitable for behaving mice. This low-cost device is easy to construct (2.5 h to build without specialized equipment). We found that the drive design produced stable high-quality recordings and continued to do so for at least 6 weeks following implantation. We validated the optetrode by quantifying, for the first time, the response of cells in the medial prefrontal cortex to local optical excitation and inhibition, probing multiple different genetically defined classes of cells in the mouse during open field exploration.

Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins.

Diverse optogenetic tools have allowed versatile control over neural activity. Many depolarizing and hyperpolarizing tools have now been developed in multiple laboratories and tested across different preparations, presenting opportunities but also making it difficult to draw direct comparisons. This challenge has been compounded by the dependence of performance on parameters such as vector, promoter, expression time, illumination, cell type and many other variables. As a result, it has become increasingly complicated for end users to select the optimal reagents for their experimental needs. For a rapidly growing field, critical figures of merit should be formalized both to establish a framework for further development and so that end users can readily understand how these standardized parameters translate into performance. Here we systematically compared microbial opsins under matched experimental conditions to extract essential principles and identify key parameters for the conduct, design and interpretation of experiments involving optogenetic techniques.

Ultrafast optogenetic control.

Channelrhodopsins such as channelrhodopsin-2 (ChR2) can drive spiking with millisecond precision in a wide variety of cells, tissues and animal species. However, several properties of this protein have limited the precision of optogenetic control. First, when ChR2 is expressed at high levels, extra spikes (for example, doublets) can occur in response to a single light pulse, with potential implications as doublets may be important for neural coding. Second, many cells cannot follow ChR2-driven spiking above the gamma (approximately 40 Hz) range in sustained trains, preventing temporally stationary optogenetic access to a broad and important neural signaling band. Finally, rapid optically driven spike trains can result in plateau potentials of 10 mV or more, causing incidental upstates with information-processing implications. We designed and validated an engineered opsin gene (ChETA) that addresses all of these limitations (profoundly reducing extra spikes, eliminating plateau potentials and allowing temporally stationary, sustained spike trains up to at least 200 Hz).

Colocalization of connexin 36 and corticotropin-releasing hormone in the mouse brain.

BACKGROUND: Gap junction proteins, connexins, are expressed in most endocrine and exocrine glands in the body and are at least in some glands crucial for the hormonal secretion. To what extent connexins are expressed in neurons releasing hormones or neuropeptides from or within the central nervous system is, however, unknown. Previous studies provide indirect evidence for gap junction coupling between subsets of neuropeptide-containing neurons in the paraventricular nucleus (PVN) of the hypothalamus. Here we employ double labeling and retrograde tracing methods to investigate to what extent neuroendocrine and neuropeptide-containing neurons of the hypothalamus and brainstem express the neuronal gap junction protein connexin 36. RESULTS: Western blot analysis showed that connexin 36 is expressed in the PVN. In bacterial artificial chromosome transgenic mice, which specifically express the reporter gene Enhanced Green Fluorescent Protein (EGFP) under the control of the connexin 36 gene promoter, EGFP expression was detected in magnocellular (neuroendocrine) and in parvocellular neurons of the PVN. Although no EGFP/connexin36 expression was seen in neurons containing oxytocin or vasopressin, EGFP/connexin36 was found in subsets of PVN neurons containing corticotropin-releasing hormone (CRH), and in somatostatin neurons located along the third ventricle. Moreover, CRH neurons in brainstem areas, including the lateral parabrachial nucleus, also expressed EGFP/connexin 36. CONCLUSION: Our data indicate that connexin 36 is expressed in subsets of neuroendocrine and CRH neurons in specific nuclei of the hypothalamus and brainstem.

Bi-stable neural state switches.

Here we describe bi-stable channelrhodopsins that convert a brief pulse of light into a stable step in membrane potential. These molecularly engineered probes nevertheless retain millisecond-scale temporal precision. Photocurrents can be precisely initiated and terminated with different colors of light, but operate at vastly longer time scales than conventional channelrhodopsins as a result of modification at the C128 position that extends the lifetime of the open state. Because of their enhanced kinetic stability, these step-function tools are also effectively responsive to light at orders of magnitude lower intensity than wild-type channelrhodopsins. These molecules therefore offer important new capabilities for a broad range of in vivo applications.