Bio21 - Research Publications

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    Advances in understanding meso-cortico-limbic-striatal systems mediating risky reward seeking.
    Piantadosi, PT ; Halladay, LR ; Radke, AK ; Holmes, A (Wiley, 2021-06)
    The risk of an aversive consequence occurring as the result of a reward-seeking action can have a profound effect on subsequent behavior. Such aversive events can be described as punishers, as they decrease the probability that the same action will be produced again in the future and increase the exploration of less risky alternatives. Punishment can involve the omission of an expected rewarding event ("negative" punishment) or the addition of an unpleasant event ("positive" punishment). Although many individuals adaptively navigate situations associated with the risk of negative or positive punishment, those suffering from substance use disorders or behavioral addictions tend to be less able to curtail addictive behaviors despite the aversive consequences associated with them. Here, we discuss the psychological processes underpinning reward seeking despite the risk of negative and positive punishment and consider how behavioral assays in animals have been employed to provide insights into the neural mechanisms underlying addictive disorders. We then review the critical contributions of dopamine signaling to punishment learning and risky reward seeking, and address the roles of interconnected ventral striatal, cortical, and amygdala regions to these processes. We conclude by discussing the ample opportunities for future study to clarify critical gaps in the literature, particularly as related to delineating neural contributions to distinct phases of the risky decision-making process.
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    Effects of optogenetic photoexcitation of infralimbic cortex inputs to the basolateral amygdala on conditioned fear and extinction.
    Bukalo, O ; Nonaka, M ; Weinholtz, CA ; Mendez, A ; Taylor, WW ; Holmes, A (Elsevier BV, 2021-01-01)
    Deficiencies in the ability to extinguish fear is a hallmark of Trauma- and stressor-related disorders, Anxiety disorders, and certain other neuropsychiatric conditions. Hence, a greater understanding of the brain mechanisms involved in the inhibition of fear is of significant translational relevance. Previous studies in rodents have shown that glutamatergic projections from the infralimbic prefrontal cortex (IL) to basolateral amygdala (BLA) play a crucial instructional role in the formation of extinction memories, and also indicate that variation in the strength of this input correlates with extinction efficacy. To further examine the relationship between the IL→BLA pathway and extinction we expressed three different titers of the excitatory opsin, channelrhodopsin (ChR2), in IL neurons and photostimulated their projections in the BLA during partial extinction training. The behavioral effects of photoexcitation differed across the titer groups: the low titer had no effect, the medium titer selectively facilitated extinction memory formation, and the high titer produced both an acute suppression of fear and a decrease in fear during (light-free) extinction retrieval. We discuss various possible explanations for these titer-specific effects, including the possibility of IL-mediated inhibition of BLA fear-encoding neurons under conditions of sufficiently strong photoexcitation. These findings further support the role of IL→BLA pathway in regulating fear and highlight the importance of methodological factors in optogenetic studies of neural circuits underling behavior.
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    Intercalated amygdala clusters orchestrate a switch in fear state.
    Hagihara, KM ; Bukalo, O ; Zeller, M ; Aksoy-Aksel, A ; Karalis, N ; Limoges, A ; Rigg, T ; Campbell, T ; Mendez, A ; Weinholtz, C ; Mahn, M ; Zweifel, LS ; Palmiter, RD ; Ehrlich, I ; Lüthi, A ; Holmes, A (Springer Science and Business Media LLC, 2021-06)
    Adaptive behaviour necessitates the formation of memories for fearful events, but also that these memories can be extinguished. Effective extinction prevents excessive and persistent reactions to perceived threat, as can occur in anxiety and 'trauma- and stressor-related' disorders1. However, although there is evidence that fear learning and extinction are mediated by distinct neural circuits, the nature of the interaction between these circuits remains poorly understood2-6. Here, through a combination of in vivo calcium imaging, functional manipulations, and slice physiology, we show that distinct inhibitory clusters of intercalated neurons (ITCs) in the mouse amygdala exert diametrically opposed roles during the acquisition and retrieval of fear extinction memory. Furthermore, we find that the ITC clusters antagonize one another through mutual synaptic inhibition and differentially access functionally distinct cortical- and midbrain-projecting amygdala output pathways. Our findings show that the balance of activity between ITC clusters represents a unique regulatory motif that orchestrates a distributed neural circuitry, which in turn regulates the switch between high- and low-fear states. These findings suggest that the ITCs have a broader role in a range of amygdala functions and associated brain states that underpins the capacity to adapt to salient environmental demands.
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    Amygdala Circuit Substrates for Stress Adaptation and Adversity.
    Zhang, W-H ; Zhang, J-Y ; Holmes, A ; Pan, B-X (Elsevier BV, 2021-05-01)
    Brain systems that promote maintenance of homeostasis in the face of stress have significant adaptive value. A growing body of work across species demonstrates a critical role for the amygdala in promoting homeostasis by regulating physiological and behavioral responses to stress. This review focuses on an emerging body of evidence that has begun to delineate the contribution of specific long-range amygdala circuits in mediating the effects of stress. After summarizing the major anatomical features of the amygdala and its connectivity to other limbic structures, we discuss recent findings from rodents showing how stress causes structural and functional remodeling of amygdala neuronal outputs to defined cortical and subcortical target regions. We also consider some of the environmental and genetic factors that have been found to moderate how the amygdala responds to stress and relate the emerging preclinical literature to the current understanding of the pathophysiology and treatment of stress-related neuropsychiatric disorders. Future effort to translate these findings to clinics may help to develop valuable tools for prevention, diagnosis, and treatment of these diseases.
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    Pharmacology of cognitive enhancers for exposure-based therapy of fear, anxiety and trauma-related disorders.
    Singewald, N ; Schmuckermair, C ; Whittle, N ; Holmes, A ; Ressler, KJ (Elsevier BV, 2015-05)
    Pathological fear and anxiety are highly debilitating and, despite considerable advances in psychotherapy and pharmacotherapy they remain insufficiently treated in many patients with PTSD, phobias, panic and other anxiety disorders. Increasing preclinical and clinical evidence indicates that pharmacological treatments including cognitive enhancers, when given as adjuncts to psychotherapeutic approaches [cognitive behavioral therapy including extinction-based exposure therapy] enhance treatment efficacy, while using anxiolytics such as benzodiazepines as adjuncts can undermine long-term treatment success. The purpose of this review is to outline the literature showing how pharmacological interventions targeting neurotransmitter systems including serotonin, dopamine, noradrenaline, histamine, glutamate, GABA, cannabinoids, neuropeptides (oxytocin, neuropeptides Y and S, opioids) and other targets (neurotrophins BDNF and FGF2, glucocorticoids, L-type-calcium channels, epigenetic modifications) as well as their downstream signaling pathways, can augment fear extinction and strengthen extinction memory persistently in preclinical models. Particularly promising approaches are discussed in regard to their effects on specific aspects of fear extinction namely, acquisition, consolidation and retrieval, including long-term protection from return of fear (relapse) phenomena like spontaneous recovery, reinstatement and renewal of fear. We also highlight the promising translational value of the preclinial research and the clinical potential of targeting certain neurochemical systems with, for example d-cycloserine, yohimbine, cortisol, and L-DOPA. The current body of research reveals important new insights into the neurobiology and neurochemistry of fear extinction and holds significant promise for pharmacologically-augmented psychotherapy as an improved approach to treat trauma and anxiety-related disorders in a more efficient and persistent way promoting enhanced symptom remission and recovery.
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    R2d2 Drives Selfish Sweeps in the House Mouse.
    Didion, JP ; Morgan, AP ; Yadgary, L ; Bell, TA ; McMullan, RC ; Ortiz de Solorzano, L ; Britton-Davidian, J ; Bult, CJ ; Campbell, KJ ; Castiglia, R ; Ching, Y-H ; Chunco, AJ ; Crowley, JJ ; Chesler, EJ ; Förster, DW ; French, JE ; Gabriel, SI ; Gatti, DM ; Garland, T ; Giagia-Athanasopoulou, EB ; Giménez, MD ; Grize, SA ; Gündüz, İ ; Holmes, A ; Hauffe, HC ; Herman, JS ; Holt, JM ; Hua, K ; Jolley, WJ ; Lindholm, AK ; López-Fuster, MJ ; Mitsainas, G ; da Luz Mathias, M ; McMillan, L ; Ramalhinho, MDGM ; Rehermann, B ; Rosshart, SP ; Searle, JB ; Shiao, M-S ; Solano, E ; Svenson, KL ; Thomas-Laemont, P ; Threadgill, DW ; Ventura, J ; Weinstock, GM ; Pomp, D ; Churchill, GA ; Pardo-Manuel de Villena, F (Oxford University Press (OUP), 2016-06)
    A selective sweep is the result of strong positive selection driving newly occurring or standing genetic variants to fixation, and can dramatically alter the pattern and distribution of allelic diversity in a population. Population-level sequencing data have enabled discoveries of selective sweeps associated with genes involved in recent adaptations in many species. In contrast, much debate but little evidence addresses whether "selfish" genes are capable of fixation-thereby leaving signatures identical to classical selective sweeps-despite being neutral or deleterious to organismal fitness. We previously described R2d2, a large copy-number variant that causes nonrandom segregation of mouse Chromosome 2 in females due to meiotic drive. Here we show population-genetic data consistent with a selfish sweep driven by alleles of R2d2 with high copy number (R2d2(HC)) in natural populations. We replicate this finding in multiple closed breeding populations from six outbred backgrounds segregating for R2d2 alleles. We find that R2d2(HC) rapidly increases in frequency, and in most cases becomes fixed in significantly fewer generations than can be explained by genetic drift. R2d2(HC) is also associated with significantly reduced litter sizes in heterozygous mothers, making it a true selfish allele. Our data provide direct evidence of populations actively undergoing selfish sweeps, and demonstrate that meiotic drive can rapidly alter the genomic landscape in favor of mutations with neutral or even negative effects on overall Darwinian fitness. Further study will reveal the incidence of selfish sweeps, and will elucidate the relative contributions of selfish genes, adaptation and genetic drift to evolution.
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    Quantitative trait loci for sensitivity to ethanol intoxication in a C57BL/6J×129S1/SvImJ inbred mouse cross.
    Chesler, EJ ; Plitt, A ; Fisher, D ; Hurd, B ; Lederle, L ; Bubier, JA ; Kiselycznyk, C ; Holmes, A (Springer Science and Business Media LLC, 2012-06)
    Individual variation in sensitivity to acute ethanol (EtOH) challenge is associated with alcohol drinking and is a predictor of alcohol abuse. Previous studies have shown that the C57BL/6J (B6) and 129S1/SvImJ (S1) inbred mouse strains differ in responses on certain measures of acute EtOH intoxication. To gain insight into genetic factors contributing to these differences, we performed quantitative trait locus (QTL) analysis of measures of EtOH-induced ataxia (accelerating rotarod), hypothermia, and loss of righting reflex (LORR) duration in a B6×S1 F2 population. We confirmed that S1 showed greater EtOH-induced hypothermia (specifically at a high dose) and longer LORR compared to B6. QTL analysis revealed several additive and interacting loci for various phenotypes, as well as examples of genotype interactions with sex. QTLs for different EtOH phenotypes were largely non-overlapping, suggesting separable genetic influences on these behaviors. The most compelling main-effect QTLs were for hypothermia on chromosome 16 and for LORR on chromosomes 4 and 6. Several QTLs overlapped with loci repeatedly linked to EtOH drinking in previous mouse studies. The architecture of the traits we examined was complex but clearly amenable to dissection in future studies. Using integrative genomics strategies, plausible functional and positional candidates may be found. Uncovering candidate genes associated with variation in these phenotypes in this population could ultimately shed light on genetic factors underlying sensitivity to EtOH intoxication and risk for alcoholism in humans.
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    Cyclooxygenase-2 inhibition reduces stress-induced affective pathology.
    Gamble-George, JC ; Baldi, R ; Halladay, L ; Kocharian, A ; Hartley, N ; Silva, CG ; Roberts, H ; Haymer, A ; Marnett, LJ ; Holmes, A ; Patel, S (eLife Sciences Publications, Ltd, 2016-05-10)
    Mood and anxiety disorders are the most prevalent psychiatric conditions and are exacerbated by stress. Recent studies have suggested cyclooxygenase-2 (COX-2) inhibition could represent a novel treatment approach or augmentation strategy for affective disorders including anxiety disorders and major depression. We show that traditional COX-2 inhibitors and a newly developed substrate-selective COX-2 inhibitor (SSCI) reduce a variety of stress-induced behavioral pathologies in mice. We found that these behavioral effects were associated with a dampening of neuronal excitability in the basolateral amygdala (BLA) ex vivo and in vivo, and were mediated by small-conductance calcium-activated potassium (SK) channel and CB1 cannabinoid receptor activation. Taken together, these data provide further support for the potential utility of SSCIs, as well as traditional COX-2 inhibitors, as novel treatment approaches for stress-related psychiatric disorders.
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    Effects of genetic deletion of the Kv4.2 voltage-gated potassium channel on murine anxiety-, fear- and stress-related behaviors.
    Kiselycznyk, C ; Hoffman, DA ; Holmes, A (Springer Science and Business Media LLC, 2012-03-02)
    BACKGROUND: Potassium channels have been proposed to play a role in mechanisms of neural plasticity, and the Kv4.2 subunit has been implicated in the regulation of action-potential back-propagation to the dendrites. Alterations in mechanisms of plasticity have been further proposed to underlie various psychiatric disorders, but the role of Kv4.2 in anxiety or depression is not well understood. METHODS: In this paper, we analyzed the phenotype Kv4.2 knockout mice based on their neurological function, on a battery of behaviors including those related to anxiety and depression, and on plasticity-related learning tasks. RESULTS: We found a novelty-induced hyperactive phenotype in knockout mice, and these mice also displayed increased reactivity to novel stimulus such as an auditory tone. No clear anxiety- or depression-related phenotype was observed, nor any alterations in learning/plasticity-based paradigms. CONCLUSIONS: We did not find clear evidence for an involvement of Kv4.2 in neuropsychiatric or plasticity-related phenotypes, but there was support for a role in Kv4.2 in dampening excitatory responses to novel stimuli.
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    Fluoxetine Facilitates Fear Extinction Through Amygdala Endocannabinoids.
    Gunduz-Cinar, O ; Flynn, S ; Brockway, E ; Kaugars, K ; Baldi, R ; Ramikie, TS ; Cinar, R ; Kunos, G ; Patel, S ; Holmes, A (Springer Science and Business Media LLC, 2016-05)
    Pharmacologically elevating brain endocannabinoids (eCBs) share anxiolytic and fear extinction-facilitating properties with classical therapeutics, including the selective serotonin reuptake inhibitor, fluoxetine. There are also known functional interactions between the eCB and serotonin systems and preliminary evidence that antidepressants cause alterations in brain eCBs. However, the potential role of eCBs in mediating the facilitatory effects of fluoxetine on fear extinction has not been established. Here, to test for a possible mechanistic contribution of eCBs to fluoxetine's proextinction effects, we integrated biochemical, electrophysiological, pharmacological, and behavioral techniques, using the extinction-impaired 129S1/Sv1mJ mouse strain. Chronic fluoxetine treatment produced a significant and selective increase in levels of anandamide in the BLA, and an associated decrease in activity of the anandamide-catabolizing enzyme, fatty acid amide hydrolase. Slice electrophysiological recordings showed that fluoxetine-induced increases in anandamide were associated with the amplification of eCB-mediated tonic constraint of inhibitory, but not excitatory, transmission in the BLA. Behaviorally, chronic fluoxetine facilitated extinction retrieval in a manner that was prevented by systemic or BLA-specific blockade of CB1 receptors. In contrast to fluoxetine, citalopram treatment did not increase BLA eCBs or facilitate extinction. Taken together, these findings reveal a novel, obligatory role for amygdala eCBs in the proextinction effects of a major pharmacotherapy for trauma- and stressor-related disorders and anxiety disorders.