ACNP 55th Annual Meeting: Poster Session IDecember 5, - Europe PMC Article - Europe PMC
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We confirmed the existence of functional synapses from posterior thalamic NT neurons in the BLA using ex vivo whole-cell patch-clamp electrophysiology. Cre mouse, and evoked synaptic release in the BLA using light. Monosynaptic currents were evoked from NT axons in the BLA by blocking action potentials using the sodium channel blocker tetrodotoxin TTX and enabling light-evoked synaptic release by blocking the voltage-activated hyperpolarizing potassium channels using 4-Aminopyridine 4-AP. We used in vivo electrophysiology and identified posterior thalamic NT-expressing neurons using photostimulation in mice expressing ChR2 in posterior thalamic NT neurons.
Neural activity was sampled during positive and negative associations. Using single unit recordings, we discovered that posterior thalamic neurons, both NT-expressing and unidentified neurons encoded tone onsets and offsets, port entries to consume sucrose solution, as well as foot shocks. However, during the association of a tone with sucrose reward, posterior thalamic NT neurons showed greater responses to port entries, relative to unidentified neurons in the posterior thalamus.
In conclusion, we have discovered that divergent populations of neurons in the BLA are differentially sensitive to NT, a neuropeptide whose action modulates BLA-mediated learning. Moreover, we identify the posterior thalamus as a source of NT to the BLA, characterize the response properties of these neurons, and provide initial evidence of a circuit mechanism whereby NT-expressing thalamic neurons likely impact the activity of BLA neurons during positive and negative associations.
Basolateral Amygdala, Neurotensin, Valence. Amongst social animals, the presence of a conspecific companion can have powerful effects on mood and behavior.
In particular, the social modulation of fear and anxiety represents a highly conserved trait, as both humans and rodents display decreases in anxiety and stress responses when an affiliative conspecific is present.
However, the neural processes underlying this social buffering phenomenon remain largely unknown. Our group has found that in mice, conspecific presence decreases freezing in both conditioned and innately fearful contexts. In order to identify neural populations that may contribute to social buffering of fear responses, we used a mouse line in which neurons expressing the immediate early gene, Arc, are indelibly labeled following interaction with a novel conspecific.
Using this line, we optogenetically re-activated socially-labelled cells in order to test the hypothesis that these neuronal populations may mediate the social modulation of fear responses. We identified a subset of cells within the infralimbic prefrontal cortex ILPFC of male and female mice that are labeled in response to interacting with a novel, ovariectomized female conspecific but not in response to a toy mouse, novel object, or food reward.
These data suggest that activation of neurons associated with an affiliative conspecific in the ILPFC may be sufficient to mediate the effects of conspecific presence on fear responses. Thus, targeting this cell population may provide novel therapeutic opportunities that harness circuits naturally engaged by social interaction in order to treat fear and anxiety-related disorders. Social Buffering, Optogenetics, Fear.
Posttraumatic stress disorder PTSD is a common and disabling psychiatric condition and current treatments possess only limited efficacy. Safe, more effective, and mechanistically novel medications are urgently needed for the treatment of PTSD and other stress-related disorders such as major depressive disorder. A large body of work implicates the neuropeptide Y NPY system as a critical regulator of stress and fear-related behaviors, and as a promising therapeutic focus for PTSD.
Therapeutic development of NPY and other peptides is limited by lack of passage of NPY across the blood-brain barrier, and by the digestion of peptides within the gastrointestinal tract. Prior work suggests that intranasal delivery may represent a viable delivery route for peptide-based therapeutics. The current study, therefore, was designed to assess the safety and initial efficacy of ascending doses of NPY delivered via an intranasal route in patients with PTSD.
The study featured a hybrid dose escalation design in which cohorts of three patients were treated at each dosing level beginning with the lowest study dose 1. Each patient underwent baseline assessments and was dosed with NPY or saline placebo on two separate treatment days that occurred one to two weeks apart. On each treatment day, patients underwent a trauma script provocation procedure 30 min following drug dosing and completed assessments throughout the day.
Two patients discontinued subsequent to the first treatment day and were not crossed over. Therefore 24 subjects completed the study at the following dosing levels: NPY was well tolerated up to and including the highest dose of 9. To examine these interactions, we compared change in scores in low dose 1.
In contrast, there were no significant increases in scores for either NPY or placebo in the low dose group. These data are suggestive of a therapeutic signal at the high but not low dose, although the study had low power to detect dose-related efficacy effects.
We show that doses up to and including 9. We found a preliminary efficacy signal at higher NPY doses. Additional studies exploring the safety, efficacy, and target engagement of NPY in humans are warranted. PTSD is characterized by a constellation of symptoms including intrusion symptoms, avoidance, negative alterations in cognition and mood, and hyperarousal. PTSD is associated with a dysregulation in threat-related processing, namely hyperarousal of the amygdala and reduced inhibitory control of the prefrontal cortex PFC.
However, relatively little is known about the molecular underpinnings of this disorder. The ability of the metabotropic glutamatergic receptors mGluRs to modulate neuronal excitability in brain circuits involved in anxiety and stress has made them a promising target for drug development for psychiatric disorders Krystal et al.
Blockade of mGluR5 has been found to produce anxiolytic effects in animal models Swanson et al. Additionally, in a postmortem sample of individuals with PTSD and controls, we aimed to investigate expression of proteins that have a functional relationship with mGluR5 and glucocorticoid GC function, which is implicated in PTSD.
Volume of distribution VT: The radiotracer was injected as bolus plus constant infusion and subjects were scanned during steady state mins post-injection. Transcriptome profiles were generated from the sequencing data and were interrogated for mGluR5 and GC related transcripts.
In the postmortem sample, we found an increased expression of Shank-1 1. Conversely, we observed decreased SGK1 Consistent with an upregulation of mGluR5, we found an upregulation of Shank-1 in an independent sample of postmortem brain tissue, a protein which anchors mGluR5 receptors to the cell surface.
In animals, cortisol upregulates SGK-1 Anacker et al. While further work is needed to confirm our findings in a larger sample and clarify the relationship between mGluR5 and GCs in vivo, our findings suggest that the mGluR5 may be implicated in the pathophysiology of PTSD and represent a novel target for drug development. Alterations in extended amygdala EA function have been linked to stress-related psychopathology, including anxiety and depressive disorders. Our laboratory has developed a non-human primate NHP model of anxious temperament AT as a means to investigate the neural and molecular mechanisms underlying the childhood risk to develop anxiety and depression.
In preadolescent rhesus monkeys, we demonstrated that two major nodes of the EA, the central nucleus of the amygdala Ce and the bed nucleus of the stria terminalis BSTare key regions in the neural circuitry mediating AT. The Ce and BST are primarily composed of striatal-like medium spiny GABAergic neurons that can be subdivided into multiple subtypes based on their neuropeptide profile.
Importantly, some studies in rodents demonstrate an uneven anterior-posterior A-P distribution of neuropeptide expression in the lateral subdivision of the Ce CeL ; however, little is known about the functional significance of this gradient in expression and whether this is a feature of neuropeptide distribution in the EA of NHPs. To further understand the cellular and molecular alterations in the EA that mediate AT it is critical: To examine selectivity in EA gene expression, we first used human and monkey microarray data from the Allen Brain Atlas to identify genes that are more highly expressed in Ce compared to striatum putamen and caudate.
Because somatostatin SST and cholecystokinin CCK were both more highly expressed in Ce than the striatum and the previous rodent studies demonstrating a role for these neuropeptides in mediating aspects of threat responding, we focused on these neuropeptides in the NHP EA. Finally, immunohistochemical staining methods were used to characterize the distribution of protein expression in relation to the mRNA expression studies.
Confirming results from the Allen Brain Institute databases, RNA-Seq analyses identified many neuropeptides with significantly greater expression in the Ce as compared to striatal regions.
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Using existing databases in combination with our rhesus monkey RNA-Seq data, we characterized genes that are preferentially expressed in the Ce as compared to the striatum.
Understanding the functional relevance of differences in the A-P expression of neuropeptide-expressing populations that are enriched in the primate EA will help direct cellular and molecular studies aimed at understanding the function of these neuropeptides, and guide the development of target-specific novel therapeutics. Anxiety, Extended Amygdala, Neuroanatomy. Furthermore, we explored whether these manifold properties differed in participants with social anxiety disorder SAD compared to healthy comparison subjects using dynamic electroencephalography EEG connectivity during an emotion regulation task.
EEG data were collected from 20 healthy participants age: During the ERT, participants were asked to look at pictures displayed on the screen, and listen to a corresponding auditory guide. Two types of pictures were on display for seven seconds in random orders: EEG data were preprocessed using Brain Vision Analyzer Brain Products, Gilching Germanyby first segmenting task trials into 7-second segments with a window size of 0.
Frequencies-of-interest were set from 1Hz to 50Hz in increments of 1Hz. The final output of each subject was averaged over trials within the same task.
As functional communication between two brain regions result in synchronized or phase-coupled EEG readouts, in this study we used weighted phase lag index WPLI computed between the times series of two channels to form EEG connectomes each of which a symmetric 34 by 34 matrix.
In order to learn the intrinsic geometry of a high-dimensional manifold, the EEG connectomes from all subjects at all time points were used to sample possible states of the manifold that is shared among all subjects. Then, graph dissimilarity space embedding is used to represent each connectome as a point in a very high-dimensional space number of dimensions equal to the number of connectiomes for each subject at each timepoint.
This is then followed by 1 manifold learning via local neighborhood reconstruction and 2 manifold embedding into a lower dimensional Euclidean space using nonlinear dimensionality reduction NDR. Once this is achieved, thought chart of any given individual can be constructed by tracing the trajectory of the time-dependent connectome of that subject for any given task.
Manifold properties can be quantified by measuring the trajectory length of a given subject's thought chart or the "spread", the area occupied by a given subject's thought chart in the state-space. We examined group differences for trajectory length and spread in the state-space during the ERT and correlations with measures of anxiety severity Liebowitz Social Anxiety Scale: Furthermore, trajectory length and spread associated with all aspects of the ERT correlated with anxiety severity scores in the total sample length x HAM-A: The present study is the first-ever demonstration of altered brain network dynamics in SAD using unsupervised manifold learning applied to dynamic EEG connectivity.
Future work will examine whether brain state-space dynamics could be used as a platform for neurofeedback applications. The prefrontal cortex PFC serves as a hub for cognitive and affective behaviors including spatial working memory and anxiety.
Two major sources of information to the PFC are provided by the ventral hippocampus vHipp and the mediodorsal thalamus MDboth of which provide glutamatergic input to this structure.
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For example, silencing vHipp to PFC terminals decreases anxiety Padilla-Coreano N et al, Neuron, and selectively impairs encoding of spatial working memory Spellman T et al, Nature, while silencing MD to PFC terminals does not affect anxiety and instead selectively impairs maintenance of spatial working memory Bolkan et al, in preparation.
However, the mechanisms by which the prefrontal cortex is able to selectively distinguish between seemingly identical neurotransmitter inputs to generate behaviorally distinct responses is unknown. We used Channel-rhodopsin ChR2 in combination with slice electrophysiology in the PFC to assess the efficacy of synaptic transmission for both projections under different input frequencies. We are currently using a combination of red-shifted and blue-light activated ChR2 to investigate whether vHipp and MD cells project to the same PFC neurons and whether synaptic transmission from these two projections is differentially affected by input frequency.
In contrast, MD to PFC inputs, while responding to a single 5-ms light pulse with a comparable amplitude to that of vHipp to PFC inputs, showed less attenuation to subsequent stimulations at 20 Hz and no failures. Our current data are consistent with a model whereby MD and vHipp inputs broadly project to overlapping pyramidal cell populations, but may be distinguished by optimal synaptic transmission at distinct frequencies.
Ketamine for Social Anxiety Disorder: Many SAD patients experience little or inadequate symptom relief with available treatments. Ketamine has robust short-term anti-depressant effects, and is particularly effective in depressed patients with comorbid anxiety.
Ketamine is a potent NMDA receptor antagonist and represents an agent with a potentially novel mechanism of action for the treatment of anxiety disorders. We sought to determine the short-term efficacy of ketamine compared to placebo in the treatment of social anxiety disorder. We conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with SAD and compared the effects of intravenous ketamine dosed 0.
Ketamine and placebo infusions were administered in a random order with a day washout period between infusions. The primary outcome of the trial was average Lebowitz Social Anxiety Scale Score for the first 3 days following infusion. All participants were asked to give a minute impromptu speech in front of a small audience at baseline and 24 hours after the intravenous infusion.
Of the 18 participants, 17 completed both infusions and 3 met criteria for current DSM-5 Major Depressive Disorder at enrollment. Eleven of 18 subjects receiving ketamine were rated as minimally improved or better on the CGI 1 day following infusion compared to 2 of 17 receiving placebo. Ketamine resulted in a significantly greater reduction in social anxiety when compared to placebo as assessed by CGI completed by blinded raters at 1 day following infusion.
A significant limitation to the self-rated anxiety during the impromptu speech is that 17 of 18 patients correctly identified when they received ketamine, suggesting that the use of saline placebo as a control for ketamine led to inadequate blinding. Analysis of change in depression symptoms, performance on the speech, social anxiety symptoms, and period effects over the full 2 weeks of symptom monitoring is pending and will be presented at the poster session.
Social anxiety SA increases during adolescence, when the salience of peer-based social evaluation peaks. Prior neuroimaging studies show that in socially anxious adolescents, peers elicit dysregulated engagement in key brain regions implicated in social cognition and affect processing Guyer et al,Lau et al.
However, SA symptoms are differentially triggered by distinct social contexts. Specifically, uncertain, rather than predictable social situations, commonly elicit SA symptoms. Thus, peer evaluation in the presence of uncertainty may be associated with distinct, yet unknown patterns of brain function that promote the affective symptoms and social biases common to SA. We recently developed an ecologically valid fMRI-based paradigm optimized to test for the effects of social evaluative uncertainty during ongoing social interactions with peers in a virtual school setting Jarcho et al, In the present study, we utilized this paradigm to determine whether neural response in SA, compared with healthy adolescents, varied during the anticipation and receipt of predictable and unpredictable peer acceptance and rejection feedback.SWIM MEET PROBLEMS!! (HIGHSCHOOL EDITION)
Before completing the fMRI paradigm, participants learned each student had a reputation for being nice, mean, or unpredictable. While scanning, participants entered classrooms with the Other Students. Participants were able to learn Other Student reputations prior to interacting at the Virtual School and subsequently reported believing these interactions involved real peers. During anticipated peer evaluation, extensive group differences in brain function emerged in medial prefrontal cortex 9, 37, 8; voxels dorsal anterior cingulate For each activation cluster, SA adolescents had heightened engagement relative to healthy adolescents.
Additionally, more severe symptoms of anxiety, measured by the Screen for Child and Anxiety Related Disorders, and more fear during the scan, were associated with greater activity. During the receipt of peer evaluation, a distinct pattern of group differences emerged in the right temporal pole 49, 16, ; 51 voxelsa brain region implicated in mentalizing and binding affective meaning to social experiences. Neither group differentiated between positive feedback from unpredictable compared with nice peers.
These results demonstrate that anticipating peer evaluation, regardless of the valence of its expected outcome, elicits heightened engagement in socio-affective processing networks among SA adolescents.
Moreover, they suggest that peer-related uncertainty may play a more central role in potentiating neural dysreguation in SAD than social rejection alone. Results also suggest further nuances in the relationship between brain function and experiences of social acceptance in normatively developing adolescents. A history of stress increases the likelihood that an individual will develop post-traumatic stress disorder PTSD.
The disorder is defined by persistent recollections of a traumatic event that are accompanied by hyperarousal, avoidance of trauma-related cues and negative changes in mood and cognition3. The limited neurobiological understanding of PTSD has been attributed, in part, to the need for improved animal models. We employed a stress enhanced fear learning SEFL paradigm that combines restraint stress with fear conditioning to precipitate traumatic memories in mice. Extinction profiles of male and female mice after SEFL were examined.
Further characterization of behavioral and molecular patterns induced by SEFL in male mice were assessed with anxiety tests, Fos immunohistochemistry and RNA-sequencing. The stress susceptible subgroup displays persistently elevated, extinction-resistant fear memory, hyperarousal, generalization, dysregulated corticosterone and altered Fos activation in PTSD-associated brain regions, the infralimbic cortex and basolateral amygdala BLAfollowing remote memory retrieval.
Importantly, behavior during SEFL training was predictive of stress susceptible and resilient animals, enabling molecular studies without the typical confound of additional behavioral phenotyping.
Transcriptome-wide analysis of the BLA revealed divergence between these two subgroups, including dysregulated transcription of genes that have been implicated in PTSD by polymorphisms specific to PTSD patients.
How often have you stopped cold after a setback? Or been demoralized by a defeat? If you are like me, more than a couple times.
This poster is designed to remind you that all too often success is just on the other side of the struggle and grind. In other words, if you want excellence, you gotta be willing to punch through a few challenges on the way. We grow when we face challenges. It can be hard to create big goals when we are surrounded by small-minded friends, family, and swimmers. That they should think smaller, and dream smaller. This is your reminder to think big. And to act big. Decide What You Want. The most freeing moment is making a firm and unwavering decision to after a goal.
To have the end goal specified, a plan to get there, and the determination to see it through. After all, it all begins with a decision. Once made, everything else seems to fall into place. This poster is designed to remind you to live up to your decision on a daily basis. Alright, alright, you might be saying. For domestic orders you will receive a tracking number when your posters are shipped out.