Publications by authors named "Nolan D Hartley"

9 Publications

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An endocannabinoid-regulated basolateral amygdala-nucleus accumbens circuit modulates sociability.

J Clin Invest 2020 04;130(4):1728-1742

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Deficits in social interaction (SI) are a core symptom of autism spectrum disorders (ASDs); however, treatments for social deficits are notably lacking. Elucidating brain circuits and neuromodulatory signaling systems that regulate sociability could facilitate a deeper understanding of ASD pathophysiology and reveal novel treatments for ASDs. Here we found that in vivo optogenetic activation of the basolateral amygdala-nucleus accumbens (BLA-NAc) glutamatergic circuit reduced SI and increased social avoidance in mice. Furthermore, we found that 2-arachidonoylglycerol (2-AG) endocannabinoid signaling reduced BLA-NAc glutamatergic activity and that pharmacological 2-AG augmentation via administration of JZL184, a monoacylglycerol lipase inhibitor, blocked SI deficits associated with in vivo BLA-NAc stimulation. Additionally, optogenetic inhibition of the BLA-NAc circuit markedly increased SI in the Shank3B-/- mouse, an ASD model with substantial SI impairment, without affecting SI in WT mice. Finally, we demonstrated that JZL184 delivered systemically or directly to the NAc also normalized SI deficits in Shank3B-/- mice, while ex vivo JZL184 application corrected aberrant NAc excitatory and inhibitory neurotransmission and reduced BLA-NAc-elicited feed-forward inhibition of NAc neurons in Shank3B-/- mice. These data reveal circuit-level and neuromodulatory mechanisms regulating social function relevant to ASDs and suggest 2-AG augmentation could reduce social deficits via modulation of excitatory and inhibitory neurotransmission in the NAc.
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http://dx.doi.org/10.1172/JCI131752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108917PMC
April 2020

Dynamic remodeling of a basolateral-to-central amygdala glutamatergic circuit across fear states.

Nat Neurosci 2019 12 11;22(12):2000-2012. Epub 2019 Nov 11.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.

Acquisition and extinction of learned fear responses utilize conserved but flexible neural circuits. Here we show that acquisition of conditioned freezing behavior is associated with dynamic remodeling of relative excitatory drive from the basolateral amygdala (BLA) away from corticotropin releasing factor-expressing (CRF) centrolateral amygdala neurons, and toward non-CRF (CRF) and somatostatin-expressing (SOM) neurons, while fear extinction training remodels this circuit back toward favoring CRF neurons. Importantly, BLA activity is required for this experience-dependent remodeling, while directed inhibition of the BLA-centrolateral amygdala circuit impairs both fear memory acquisition and extinction memory retrieval. Additionally, ectopic excitation of CRF neurons impairs fear memory acquisition and facilities extinction, whereas CRF neuron inhibition impairs extinction memory retrieval, supporting the notion that CRF neurons serve to inhibit learned freezing behavior. These data suggest that afferent-specific dynamic remodeling of relative excitatory drive to functionally distinct subcortical neuronal output populations represents an important mechanism underlying experience-dependent modification of behavioral selection.
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http://dx.doi.org/10.1038/s41593-019-0528-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6884697PMC
December 2019

Sigma-1 receptor ligands inhibit catecholamine secretion from adrenal chromaffin cells due to block of nicotinic acetylcholine receptors.

J Neurochem 2017 10 19;143(2):171-182. Epub 2017 Sep 19.

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Adrenal chromaffin cells (ACCs) are the neuroendocrine arm of the sympathetic nervous system and key mediators of the physiological stress response. Acetylcholine (ACh) released from preganglionic splanchnic nerves activates nicotinic acetylcholine receptors (nAChRs) on chromaffin cells causing membrane depolarization, opening voltage-gated Ca channels (VGCC), and exocytosis of catecholamines and neuropeptides. The serotonin transporter is expressed in ACCs and interacts with 5-HT receptors to control secretion. In addition to blocking the serotonin transporter, some selective serotonin reuptake inhibitors (SSRIs) are also agonists at sigma-1 receptors which function as intracellular chaperone proteins and can translocate to the plasma membrane to modulate ion channels. Therefore, we investigated whether SSRIs and other sigma-1 receptor ligands can modulate stimulus-secretion coupling in ACCs. Escitalopram and fluvoxamine (100 nM to 1 μM) reversibly inhibited nAChR currents. The sigma-1 receptor antagonists NE-100 and BD-1047 also blocked nAChR currents (≈ 50% block at 100 nM) as did PRE-084, a sigma-1 receptor agonist. Block of nAChR currents by fluvoxamine and NE-100 was not additive suggesting a common site of action. VGCC currents were unaffected by the drugs. Neither the increase in cytosolic [Ca ] nor the resulting catecholamine secretion evoked by direct membrane depolarization to bypass nAChRs was altered by fluvoxamine or NE-100. However, both Ca entry and catecholamine secretion evoked by the cholinergic agonist carbachol were significantly reduced by fluvoxamine or NE-100. Together, our data suggest that sigma-1 receptors do not acutely regulate catecholamine secretion. Rather, SSRIs and other sigma-1 receptor ligands inhibit secretion evoked by cholinergic stimulation because of direct block of Ca entry via nAChRs.
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http://dx.doi.org/10.1111/jnc.14149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630514PMC
October 2017

Functional Redundancy Between Canonical Endocannabinoid Signaling Systems in the Modulation of Anxiety.

Biol Psychiatry 2017 Oct 15;82(7):488-499. Epub 2017 Mar 15.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee. Electronic address:

Background: Increasing the available repertoire of effective treatments for mood and anxiety disorders represents a critical unmet need. Pharmacological augmentation of endogenous cannabinoid (eCB) signaling has been suggested to represent a novel approach to the treatment of anxiety disorders; however, the functional interactions between two canonical eCB pathways mediated via anandamide (N-arachidonylethanolamine [AEA]) and 2-arachidonoylglycerol (2-AG) in the regulation of anxiety are not well understood.

Methods: We utilized pharmacological augmentation and depletion combined with behavioral and electrophysiological approaches to probe the role of 2-AG signaling in the modulation of stress-induced anxiety and the functional redundancy between AEA and 2-AG signaling in the modulation of anxiety-like behaviors in mice.

Results: Selective 2-AG augmentation reduced anxiety in the light/dark box assay and prevented stress-induced increases in anxiety associated with limbic AEA deficiency. In contrast, acute 2-AG depletion increased anxiety-like behaviors, which was normalized by selective pharmacological augmentation of AEA signaling and via direct cannabinoid receptor 1 stimulation with Δ-tetrahydrocannabinol. Electrophysiological studies revealed 2-AG modulation of amygdala glutamatergic transmission as a key synaptic correlate of the anxiolytic effects of 2-AG augmentation.

Conclusions: Although AEA and 2-AG likely subserve distinct physiological roles, a pharmacological and functional redundancy between these canonical eCB signaling pathways exists in the modulation of anxiety-like behaviors. These data support development of eCB-based treatment approaches for mood and anxiety disorders and suggest a potentially wider therapeutic overlap between AEA and 2-AG augmentation approaches than was previously appreciated.
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http://dx.doi.org/10.1016/j.biopsych.2017.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5585044PMC
October 2017

Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.

Nat Commun 2017 03 28;8:14782. Epub 2017 Mar 28.

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.

Stress is a ubiquitous risk factor for the exacerbation and development of affective disorders including major depression and posttraumatic stress disorder. Understanding the neurobiological mechanisms conferring resilience to the adverse consequences of stress could have broad implications for the treatment and prevention of mood and anxiety disorders. We utilize laboratory mice and their innate inter-individual differences in stress-susceptibility to demonstrate a critical role for the endogenous cannabinoid 2-arachidonoylglycerol (2-AG) in stress-resilience. Specifically, systemic 2-AG augmentation is associated with a stress-resilient phenotype and enhances resilience in previously susceptible mice, while systemic 2-AG depletion or CB1 receptor blockade increases susceptibility in previously resilient mice. Moreover, stress-resilience is associated with increased phasic 2-AG-mediated synaptic suppression at ventral hippocampal-amygdala glutamatergic synapses and amygdala-specific 2-AG depletion impairs successful adaptation to repeated stress. These data indicate amygdala 2-AG signalling mechanisms promote resilience to adverse effects of acute traumatic stress and facilitate adaptation to repeated stress exposure.
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http://dx.doi.org/10.1038/ncomms14782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379055PMC
March 2017

Prefrontal inputs to the amygdala instruct fear extinction memory formation.

Sci Adv 2015 Jul 31;1(6). Epub 2015 Jul 31.

Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20853, USA.

Persistent anxiety after a psychological trauma is a hallmark of many anxiety disorders. However, the neural circuits mediating the extinction of traumatic fear memories remain incompletely understood. We show that selective, in vivo stimulation of the ventromedial prefrontal cortex (vmPFC)-amygdala pathway facilitated extinction memory formation, but not retrieval. Conversely, silencing the vmPFC-amygdala pathway impaired extinction formation and reduced extinction-induced amygdala activity. Our data demonstrate a critical instructional role for the vmPFC-amygdala circuit in the formation of extinction memories. These findings advance our understanding of the neural basis of persistent fear, with implications for posttraumatic stress disorder and other anxiety disorders.
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http://dx.doi.org/10.1126/sciadv.1500251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618669PMC
July 2015

Multiple mechanistically distinct modes of endocannabinoid mobilization at central amygdala glutamatergic synapses.

Neuron 2014 Mar;81(5):1111-1125

Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN 37212, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37212, USA; Vanderbilt Brain Institute, Vanderbilt University School of Medicine, Nashville, TN 37212, USA. Electronic address:

The central amygdala (CeA) is a key structure at the limbic-motor interface regulating stress responses and emotional learning. Endocannabinoid (eCB) signaling is heavily implicated in the regulation of stress-response physiology and emotional learning processes; however, the role of eCBs in the modulation of synaptic efficacy in the CeA is not well understood. Here we describe the subcellular localization of CB1 cannabinoid receptors and eCB synthetic machinery at glutamatergic synapses in the CeA and find that CeA neurons exhibit multiple mechanistically and temporally distinct modes of postsynaptic eCB mobilization. These data identify a prominent role for eCBs in the modulation of excitatory drive to CeA neurons and provide insight into the mechanisms by which eCB signaling and exogenous cannabinoids could regulate stress responses and emotional learning.
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http://dx.doi.org/10.1016/j.neuron.2014.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3955008PMC
March 2014

Substrate-selective COX-2 inhibition decreases anxiety via endocannabinoid activation.

Nat Neurosci 2013 Sep 4;16(9):1291-8. Epub 2013 Aug 4.

A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

Augmentation of endogenous cannabinoid (eCB) signaling represents an emerging approach to the treatment of affective disorders. Cyclooxygenase-2 (COX-2) oxygenates arachidonic acid to form prostaglandins, but also inactivates eCBs in vitro. However, the viability of COX-2 as a therapeutic target for in vivo eCB augmentation has not been explored. Using medicinal chemistry and in vivo analytical and behavioral pharmacological approaches, we found that COX-2 is important for the regulation of eCB levels in vivo. We used a pharmacological strategy involving substrate-selective inhibition of COX-2 to augment eCB signaling without affecting related non-eCB lipids or prostaglandin synthesis. Behaviorally, substrate-selective inhibition of COX-2 reduced anxiety-like behaviors in mice via increased eCB signaling. Our data suggest a key role for COX-2 in the regulation of eCB signaling and indicate that substrate-selective pharmacology represents a viable approach for eCB augmentation with broad therapeutic potential.
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http://dx.doi.org/10.1038/nn.3480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788575PMC
September 2013

Dissociable effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in the novelty-induced hypophagia test in mice.

Psychopharmacology (Berl) 2013 Aug 13;228(3):401-9. Epub 2013 Mar 13.

Department of Psychiatry, Vanderbilt University School of Medicine, Robinson Research Building, Rm 724B, Nashville, TN 37212, USA.

Rationale: Central CB1 cannabinoid receptors regulate anxiety-like and appetitive consummatory behaviors. Pharmacological antagonism/inverse-agonism of CB1 receptors increases anxiety and decreases appetitive behaviors; however, neither well-defined dose nor context dependence of these effects has been simultaneously assessed in one behavioral assay.

Objectives: We sought to determine the context and dose dependence of the effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in a model that allowed for simultaneous detection of anxiety-like and consummatory-related behaviors.

Methods: We determined the effects of the CB1 receptor antagonist/inverse-agonist, rimonabant, in the novelty-induced hypophagia (NIH) assay in juvenile male ICR mice.

Results: Rimonabant dose-dependently decreased consumption of a palatable reward solution completely independent of contextual novelty. Grooming and scratching behavior was also increased by rimonabant in a context-independent manner. In contrast, rimonabant increased feeding latency, a measure of anxiety-like behaviors, only in a novel, mildly anxiogenic context. The effects of rimonabant were specific since no effects of rimonabant on despair-like behavior were observed in the tail suspension assay. Blockade of CB2 receptors had no effect on novelty-induced increases in feeding latency or palatable food consumption.

Conclusions: Our findings indicate that CB1 receptor blockade decreases the hedonic value of palatable food irrespective of environmental novelty, whereas the anxiogenic-like effects are highly context-dependent. Blockade of CB2 receptors does not regulate either anxiety-like or consummatory behaviors in the NIH assay. These findings suggest that rimonabant modulates distinct and dissociable neural processes regulating anxiety and consummatory behavior to sculpt complex and context-dependent behavioral repertories.
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http://dx.doi.org/10.1007/s00213-013-3042-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3707973PMC
August 2013
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