Alzheimer's Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.

A zinc finger transcription factor enables social behaviors while controlling transposable elements and immune response in prefrontal cortex.

The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in rodent prefrontal cortex was previously demonstrated to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Following viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, inversion of ZFP189-mediated transcription in this brain area, achieved by viral delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. RNA sequencing of virally manipulated prefrontal cortex tissues reveals that ZFP189 transcription factors of opposing regulatory function (ZFP189WT versus ZFP189VPR) have opposite influence on the expression of genetic transposable elements as well as genes that participate in adaptive immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for complex social behaviors while regulating transposable element-rich regions of DNA and the expression of immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal's capacity for functioning in social groups.

Revision of Alzheimer's diagnostic criteria or relocation of the Potemkin village.

The recently announced revision of the Alzheimer's disease (AD) diagnostic ATN classification adds to an already existing disregard for clinical assessment the rejection of image-based in vivo assessment of the brain's condition. The revision suggests that the diagnosis of AD should be based solely on the presence of cerebral amyloid-beta and tau, indicated by the "A" and "T". The "N", which stands for neurodegeneration - detected by imaging - should no longer be given importance, except that A+ ± T + = AD with amyloid PET being the main method for demonstrating A+ . We believe this is an artificial and misleading suggestion. It is artificial because it relies on biomarkers whose significance remains obscure and where the detection of "A" is based on a never-validated PET method using a tracer that marks much more than amyloid-beta. It is misleading because many patients without dementia will be falsely classified as having AD, but nonetheless candidates for passive immunotherapy, which may be more harmful than beneficial, and sometimes fatal.

Histone H1x in mouse ventral hippocampus correlates with, but does not cause behavioral adaptations to stress.

Prior research has identified differential protein expression levels of linker histone H1x within the ventral hippocampus (vHipp) of stress-susceptible versus stress-resilient mice. These mice are behaviorally classified based on their divergent responses to chronic social stress. Here, we sought to determine whether elevated vHipp H1x protein levels directly contribute to these diverging behavioral adaptations to stress. First, we demonstrate that stress-susceptible mice uniquely express elevated vHipp H1x protein levels following chronic stress. Given that linker histones coordinate heterochromatin compaction, we hypothesize that elevated levels of H1x in the vHipp may impede pro-resilience transcriptional adaptations and prevent development of the resilient phenotype following social stress. To test this, 8-10-week-old male C57BL/6J mice were randomly assigned to stressed and unstressed groups undergoing 10 days of chronic social defeat stress (CSDS) or single housing respectively. Following CSDS, mice were classified as susceptible versus resilient based on their social interaction behaviors. We synthesized a viral overexpression (OE) vector for H1x and transduced experimental mice with either H1x or control GFP within vHipp. Following viral delivery, we conducted social, anxiety-like, and memory-reliant behavior tests on distinct cohorts of mice. We found no behavioral adaptations following H1x OE compared to GFP controls in susceptible, resilient, or unstressed mice. In sum, although we confirm vHipp protein levels of H1x correlate with susceptibility to social stress, we observe no significant behavioral consequence of H1x OE. Thus, we conclude elevated levels of H1x are correlated with, but are not singularly sufficient to drive development of behavioral adaptations to stress.

The Anti-Amyloid Monoclonal Antibody Lecanemab: 16 Cautionary Notes.

After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab's efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-ß and its derivatives are not the main causative agents of Alzheimer's disease dementia.

A zinc finger transcription factor tunes social behaviors by controlling transposable elements and immune response in prefrontal cortex.

The neurobiological origins of social behaviors are incompletely understood. Here we utilized synthetic biology approaches to reprogram the function of ZFP189, a transcription factor whose expression and function in the rodent prefrontal cortex was previously determined to be protective against stress-induced social deficits. We created novel synthetic ZFP189 transcription factors including ZFP189VPR, which activates the transcription of target genes and therefore exerts opposite functional control from the endogenous, transcriptionally repressive ZFP189WT. Upon viral delivery of these synthetic ZFP189 transcription factors to mouse prefrontal cortex, we observe that ZFP189-mediated transcriptional control promotes mature dendritic spine morphology on transduced pyramidal neurons. Interestingly, dysregulation of ZFP189-mediated transcription in this brain area, achieved by delivery of synthetic ZFP189VPR, precipitates social behavioral deficits in terms of social interaction, motivation, and the cognition necessary for the maintenance of social hierarchy, without other observable behavioral deficits. By performing RNA sequencing in virally manipulated prefrontal cortex tissues, we discover that ZFP189 transcription factors of opposing regulatory function have opposite influence on the expression of genetic transposable elements as well as genes that participate in immune functions. Collectively, this work reveals that ZFP189 function in the prefrontal cortex coordinates structural and transcriptional neuroadaptations necessary for social behaviors by binding transposable element-rich regions of DNA to regulate immune-related genes. Given the evidence for a co-evolution of social behavior and the brain immune response, we posit that ZFP189 may have evolved to augment brain transposon-associated immune function as a way of enhancing an animal's capacity for functioning in social groups.

Transcriptional control of nucleus accumbens neuronal excitability by retinoid X receptor alpha tunes sensitivity to drug rewards.

The complex nature of the transcriptional networks underlying addictive behaviors suggests intricate cooperation between diverse gene regulation mechanisms that go beyond canonical activity-dependent pathways. Here, we implicate in this process a nuclear receptor transcription factor, retinoid X receptor alpha (RXRα), which we initially identified bioinformatically as associated with addiction-like behaviors. In the nucleus accumbens (NAc) of male and female mice, we show that although its own expression remains unaltered after cocaine exposure, RXRα controls plasticity- and addiction-relevant transcriptional programs in both dopamine receptor D1- and D2-expressing medium spiny neurons, which in turn modulate intrinsic excitability and synaptic activity of these NAc cell types. Behaviorally, bidirectional viral and pharmacological manipulation of RXRα regulates drug reward sensitivity in both non-operant and operant paradigms. Together, this study demonstrates a key role for NAc RXRα in promoting drug addiction and paves the way for future studies of rexinoid signaling in psychiatric disease states.

CREB Binding at the Zfp189 Promoter Within Medium Spiny Neuron Subtypes Differentially Regulates Behavioral and Physiological Adaptations Over the Course of Cocaine Use.

BACKGROUND: Over the course of chronic drug use, brain transcriptional neuroadaptation is thought to contribute to a change in drug use behavior over time. The function of the transcription factor CREB (cAMP response element binding protein) within the nucleus accumbens (NAc) has been well documented in opposing the rewarding properties of many classes of drugs, yet the gene targets through which CREB causally manifests these lasting neuroadaptations remain unknown. Here, we identify zinc finger protein 189 (Zfp189) as a CREB target gene that is transcriptionally responsive to acute and chronic cocaine use within the NAc of mice. METHODS: To investigate the role of the CREB-Zfp189 interaction in cocaine use, we virally delivered modified clustered regularly interspaced short palindromic repeats (CRISPR)/dCas9 constructs capable of selectively localizing CREB to the Zfp189 gene promoter in the NAc of mice. RESULTS: We observed that CREB binding to the Zfp189 promoter increased Zfp189 expression and diminished the reinforcing responses to cocaine. Furthermore, we showed that NAc Zfp189 expression increased within D1 medium spiny neurons in response to acute cocaine but increased in both D1- and D2-expressing medium spiny neurons in response to chronic cocaine. CREB-mediated induction of Zfp189 potentiated electrophysiological activity of D1- and D2-expressing medium spiny neurons, recapitulating the known effect of CREB on these neurons. Finally, targeting CREB to the Zfp189 promoter within NAc Drd2-expressing neurons, but not Drd1-expressing neurons, was sufficient to diminish cocaine-conditioned behaviors. CONCLUSIONS: Together, these findings point to the CREB-Zfp189 interaction within the NAc Drd2+ neurons as a molecular signature of chronic cocaine use that is causal in counteracting the reinforcing effects of cocaine.

Rescue of deficits by Brwd1 copy number restoration in the Ts65Dn mouse model of Down syndrome.

With an incidence of ~1 in 800 births, Down syndrome (DS) is the most common chromosomal condition linked to intellectual disability worldwide. While the genetic basis of DS has been identified as a triplication of chromosome 21 (HSA21), the genes encoded from HSA21 that directly contribute to cognitive deficits remain incompletely understood. Here, we found that the HSA21-encoded chromatin effector, BRWD1, was upregulated in neurons derived from iPS cells from an individual with Down syndrome and brain of trisomic mice. We showed that selective copy number restoration of Brwd1 in trisomic animals rescued deficits in hippocampal LTP, cognition and gene expression. We demonstrated that Brwd1 tightly binds the BAF chromatin remodeling complex, and that increased Brwd1 expression promotes BAF genomic mistargeting. Importantly, Brwd1 renormalization rescued aberrant BAF localization, along with associated changes in chromatin accessibility and gene expression. These findings establish BRWD1 as a key epigenomic mediator of normal neurodevelopment and an important contributor to DS-related phenotypes.

Comparative Transcriptional Analyses in the Nucleus Accumbens Identifies RGS2 as a Key Mediator of Depression-Related Behavior.

BACKGROUND: Major depressive disorder is one of the most commonly diagnosed mental illnesses worldwide, with a higher prevalence in women than in men. Although currently available pharmacological therapeutics help many individuals, they are not effective for most. Animal models have been important for the discovery of molecular alterations in stress and depression, but difficulties in adapting animal models of depression for females has impeded progress in developing novel therapeutic treatments that may be more efficacious for women. METHODS: Using the California mouse social defeat model, we took a multidisciplinary approach to identify stress-sensitive molecular targets that have translational relevance for women. We determined the impact of stress on transcriptional profiles in male and female California mouse nucleus accumbens (NAc) and compared these results with data from postmortem samples of the NAc from men and women diagnosed with major depressive disorder. RESULTS: Our cross-species computational analyses identified Rgs2 (regulator of G protein signaling 2) as a transcript downregulated by social defeat stress in female California mice and in women with major depressive disorder. RGS2 plays a key role in signal regulation of neuropeptide and neurotransmitter receptors. Viral vector-mediated overexpression of Rgs2 in the NAc restored social approach and sucrose preference in stressed female California mice. CONCLUSIONS: These studies show that Rgs2 acting in the NAc has functional properties that translate to changes in anxiety- and depression-related behavior. Future studies should investigate whether targeting Rgs2 represents a novel target for treatment-resistant depression in women.

A viral toolbox for conditional and transneuronal gene expression in zebrafish.

The zebrafish is an important model in systems neuroscience but viral tools to dissect the structure and function of neuronal circuitry are not established. We developed methods for efficient gene transfer and retrograde tracing in adult and larval zebrafish by herpes simplex viruses (HSV1). HSV1 was combined with the Gal4/UAS system to target cell types with high spatial, temporal, and molecular specificity. We also established methods for efficient transneuronal tracing by modified rabies viruses in zebrafish. We demonstrate that HSV1 and rabies viruses can be used to visualize and manipulate genetically or anatomically identified neurons within and across different brain areas of adult and larval zebrafish. An expandable library of viruses is provided to express fluorescent proteins, calcium indicators, optogenetic probes, toxins and other molecular tools. This toolbox creates new opportunities to interrogate neuronal circuits in zebrafish through combinations of genetic and viral approaches.

Gene-Targeted, CREB-Mediated Induction of ΔFosB Controls Distinct Downstream Transcriptional Patterns Within D1 and D2 Medium Spiny Neurons.

BACKGROUND: The onset and persistence of addiction phenotypes are, in part, mediated by transcriptional mechanisms in the brain that affect gene expression and, subsequently, neural circuitry. ΔFosB is a transcription factor that accumulates in the nucleus accumbens (NAc)-a brain region responsible for coordinating reward and motivation-after exposure to virtually every known rewarding substance, including cocaine and opioids. ΔFosB has also been shown to directly control gene transcription and behavior downstream of both cocaine and opioid exposure, but with potentially different roles in D1 and D2 medium spiny neurons (MSNs) in NAc. METHODS: To clarify MSN subtype-specific roles for ΔFosB and investigate how these coordinate the actions of distinct classes of addictive drugs in NAc, we developed a CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9-based epigenome editing tool to induce endogenous ΔFosB expression in vivo in the absence of drug exposure. After inducing ΔFosB in D1- or D2-MSNs or both, we performed RNA sequencing on bulk male and female NAc tissue (n = 6-8/group). RESULTS: We found that ΔFosB induction elicits distinct transcriptional profiles in NAc by MSN subtype and by sex, establishing for the first time that ΔFosB mediates different transcriptional effects in males versus females. We also demonstrated that changes in D1-MSNs, but not those in D2-MSNs or both, significantly recapitulate changes in gene expression induced by cocaine self-administration. CONCLUSIONS: Together, these findings demonstrate the efficacy of a novel molecular tool for studying cell type-specific transcriptional mechanisms and shed new light on the activity of ΔFosB, a critical transcriptional regulator of drug addiction.

Serum- and glucocorticoid-inducible kinase 1 activity in ventral tegmental area dopamine neurons regulates cocaine conditioned place preference but not cocaine self-administration.

Drugs of abuse regulate the activity of the mesolimbic dopamine (DA) system, and drug-induced changes in ventral tegmental area (VTA) cellular activity and gene regulation are linked to behavioral outputs associated with addiction. Previous work from our lab determined that VTA serum- and glucocorticoid-inducible kinase 1 (SGK1) transcription and catalytic activity were increased by repeated cocaine administration; however, it was unknown if these biochemical changes contributed to cocaine-elicited behaviors. Using transgenic and viral-mediated manipulations, we investigated the role of VTA SGK1 catalytic activity in regulating cocaine conditioned place preference and self-administration. We showed intra-VTA infusion of a catalytically inactive SGK1 mutant (K127Q) significantly decreased cocaine conditioned place preference (CPP). Further, we found that K127Q expression in VTA DA neurons significantly decreased cocaine CPP, while this same manipulation in VTA GABA neurons had no effect. However, blunted VTA DA SGK1 catalytic activity did not alter cocaine self-administration. Altogether, these studies identify the specific VTA cells critical for SGK1-mediated effects on cocaine CPP but not self-administration.

A highly homogeneous polymer composed of tetrahedron-like monomers for high-isotropy expansion microscopy.

Expansion microscopy (ExM) physically magnifies biological specimens to enable nanoscale-resolution imaging using conventional microscopes. Current ExM methods permeate specimens with free-radical-chain-growth-polymerized polyacrylate hydrogels, whose network structure limits the local isotropy of expansion as well as the preservation of morphology and shape at the nanoscale. Here we report that ExM is possible using hydrogels that have a more homogeneous network structure, assembled via non-radical terminal linking of tetrahedral monomers. As with earlier forms of ExM, such 'tetra-gel'-embedded specimens can be iteratively expanded for greater physical magnification. Iterative tetra-gel expansion of herpes simplex virus type 1 (HSV-1) virions by ~10× in linear dimension results in a median spatial error of 9.2 nm for localizing the viral envelope layer, rather than 14.3 nm from earlier versions of ExM. Moreover, tetra-gel-based expansion better preserves the virion spherical shape. Thus, tetra-gels may support ExM with reduced spatial errors and improved local isotropy, pointing the way towards single-biomolecule accuracy ExM.

Nucleus Accumbens Medium Spiny Neuron Subtypes Differentially Regulate Stress-Associated Alterations in Sleep Architecture.

BACKGROUND: Stress is implicated in the pathophysiology of major depression and posttraumatic stress disorder. These conditions share core features, including motivational deficits, heighted anxiety, and sleep dysregulation. Chronic stress produces these same features in rodents, with some individuals being susceptible or resilient, as seen in humans. While stress-induced neuroadaptations within the nucleus accumbens are implicated in susceptibility-related dysregulation of motivational and emotional behaviors, their effects on sleep are unclear. METHODS: We used chemogenetics (DREADDs [designer receptors exclusively activated by designer drugs]) to examine the effects of selective alterations in activity of nucleus accumbens medium spiny neurons expressing dopamine D1 receptors (D1-MSNs) or dopamine D2 receptors (D2-MSNs) on sleep-related end points. Mice were implanted with wireless transmitters enabling continuous collection of data to quantify vigilance states over a 20-day test period. Parallel cohorts were examined in behavioral tests assessing stress susceptibility. RESULTS: D1- and D2-MSNs play dissociable roles in sleep regulation. Stimulation of inhibitory or excitatory DREADDs expressed in D1-MSNs exclusively affects rapid eye movement sleep, whereas targeting D2-MSNs affects slow wave sleep. The combined effects of D1-MSN inhibition and D2-MSN activation on sleep resemble those of chronic social defeat stress. Alterations in D1-MSN function also affect stress susceptibility in social behavior tests. Elevation of CREB (cAMP response element-binding protein) within D1-MSNs is sufficient to produce stress-like effects on rapid eye movement sleep. CONCLUSIONS: In addition to regulation of motivational and emotional behaviors, the nucleus accumbens also influences sleep, an end point with high translational relevance. These findings provide a neural basis for comorbidity in key features of stress-related illness.

A Basomedial Amygdala to Intercalated Cells Microcircuit Expressing PACAP and Its Receptor PAC1 Regulates Contextual Fear.

Trauma can cause dysfunctional fear regulation leading some people to develop disorders, such as post-traumatic stress disorder (PTSD). The amygdala regulates fear, whereas PACAP (pituitary adenylate activating peptide) and PAC1 receptors are linked to PTSD symptom severity at genetic/epigenetic levels, with a strong link in females with PTSD. We discovered a PACAPergic projection from the basomedial amygdala (BMA) to the medial intercalated cells (mICCs) in adult mice. In vivo optogenetic stimulation of this pathway increased CFOS expression in mICCs, decreased fear recall, and increased fear extinction. Selective deletion of PAC1 receptors from the mICCs in females reduced fear acquisition, but enhanced fear generalization and reduced fear extinction in males. Optogenetic stimulation of the BMA-mICC PACAPergic pathway produced EPSCs in mICC neurons, which were enhanced by the PAC1 receptor antagonist, PACAP 6-38. Our findings show that mICCs modulate contextual fear in a dynamic and sex-dependent manner via a microcircuit containing the BMA and mICCs, and in a manner that was dependent on behavioral state.SIGNIFICANCE STATEMENT Traumatic stress can affect different aspects of fear behaviors, including fear learning, generalization of learned fear to novel contexts, how the fear of the original context is recalled, and how fear is reduced over time. While the amygdala has been studied for its role in regulation of different aspects of fear, the molecular circuitry of this structure is quite complex. In addition, aspects of fear can be modulated differently in males and females. Our findings show that a specific circuitry containing the neuropeptide PACAP and its receptor, PAC1, regulates various aspects of fear, including acquisition, generalization, recall, and extinction in a sexually dimorphic manner, characterizing a novel pathway that modulates traumatic fear.

Regulation of impulsive and aggressive behaviours by a novel lncRNA.

High impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours.

Neuroadaptations in the dorsal hippocampus underlie cocaine seeking during prolonged abstinence.

Relapse vulnerability in substance use disorder is attributed to persistent cue-induced drug seeking that intensifies (or "incubates") during drug abstinence. Incubated cocaine seeking has been observed in both humans with cocaine use disorder and in preclinical relapse models. This persistent relapse vulnerability is mediated by neuroadaptations in brain regions involved in reward and motivation. The dorsal hippocampus (DH) is involved in context-induced reinstatement of cocaine seeking but the role of the DH in cocaine seeking during prolonged abstinence has not been investigated. Here we found that transforming growth factor-ß (TGF-ß) superfamily member activin A is increased in the DH on abstinence day (AD) 30 but not AD1 following extended-access cocaine self-administration compared to saline controls. Moreover, activin A does not affect cocaine seeking on AD1 but regulates cocaine seeking on AD30 in a bidirectional manner. Next, we found that activin A regulates phosphorylation of NMDA receptor (NMDAR) subunit GluN2B and that GluN2B-containing NMDARs also regulate expression of cocaine seeking on AD30. Activin A and GluN2B-containing NMDARs have both previously been implicated in hippocampal synaptic plasticity. Therefore, we examined synaptic strength in the DH during prolonged abstinence and observed an increase in moderate long-term potentiation (LTP) in cocaine-treated rats compared to saline controls. Lastly, we examined the role of DH projections to the lateral septum (LS), a brain region implicated in cocaine seeking and found that DH projections to the LS govern cocaine seeking on AD30. Taken together, this study demonstrates a role for the DH in relapse behavior following prolonged abstinence from cocaine self-administration.

Genome-wide translational profiling of amygdala Crh-expressing neurons reveals role for CREB in fear extinction learning.

Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits. Neurons expressing the corticotropin-releasing hormone gene (Crh) in central amygdala (CeA) are implicated in threat regulation, yet little is known of cell type-specific gene pathways mediating adaptive learning. We translationally profiled the transcriptome of CeA Crh-expressing cells (Crh neurons) after fear conditioning or extinction in mice using translating ribosome affinity purification (TRAP) and RNAseq. Differential gene expression and co-expression network analyses identified diverse networks activated or inhibited by fear vs extinction. Upstream regulator analysis demonstrated that extinction associates with reduced CREB expression, and viral vector-induced increased CREB expression in Crh neurons increased fear expression and inhibited extinction. These findings suggest that CREB, within CeA Crh neurons, may function as a molecular switch that regulates expression of fear and its extinction. Cell-type specific translational analyses may suggest targets useful for understanding and treating stress-related psychiatric illness.

Author Correction: Genome-wide translational profiling of amygdala Crh-expressing neurons reveals role for CREB in fear extinction learning.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.