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Sex-Dependent Modulation of Anxiety and Fear by 5-HT Receptors in the Bed Nucleus of the Stria Terminalis.
Marcinkiewcz CA, Bierlein-De La Rosa G, Dorrier CE, McKnight M, DiBerto JF, Pati D, Gianessi CA, Hon OJ, Tipton G, McElligott ZA, Delpire E, Kash TL
(2019) ACS Chem Neurosci 10: 3154-3166
MeSH Terms: Animals, Anxiety, Behavior, Animal, Fear, Feeding Behavior, Female, Gene Knockdown Techniques, Male, Mice, Mice, Transgenic, Motor Activity, Neurons, Receptor, Serotonin, 5-HT1A, Septal Nuclei, Sex Factors
Show Abstract · Added June 28, 2019
Serotonin (5-hydroxytryptamine; 5-HT) coordinates behavioral responses to stress through a variety of presynaptic and postsynaptic receptors distributed across functionally diverse neuronal networks in the central nervous system. Efferent 5-HT projections from the dorsal raphe nucleus (DRN) to the bed nucleus of the stria terminalis (BNST) are generally thought to enhance anxiety and aversive learning by activating 5-HT receptor (5-HTR) signaling in the BNST, although an opposing role for postsynaptic 5-HT receptors has recently been suggested. In the present study, we sought to delineate a role for postsynaptic 5-HT receptors in the BNST in aversive behaviors using a conditional knockdown of the 5-HT receptor. Both males and females were tested to dissect out sex-specific effects. We found that male mice have significantly reduced fear memory recall relative to female mice and inactivation of 5-HT receptor in the BNST increases contextual fear conditioning in male mice so that they resemble the females. This coincided with an increase in neuronal excitability in males, suggesting that 5-HT receptor deletion may enhance contextual fear recall by disinhibiting fear memory circuits in the BNST. Interestingly, 5-HT receptor knockdown did not significantly alter anxiety-like behavior in male or female mice, which is in agreement with previous findings that anxiety and fear are modulated by dissociable circuits in the BNST. Overall, these results suggest that BNST 5-HT receptors do not significantly alter behavior under basal conditions, but can act as a molecular brake that buffer against excessive activation of aversive circuits in more threatening contexts.
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15 MeSH Terms
Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.
Shi CH, Rubel C, Soss SE, Sanchez-Hodge R, Zhang S, Madrigal SC, Ravi S, McDonough H, Page RC, Chazin WJ, Patterson C, Mao CY, Willis MS, Luo HY, Li YS, Stevens DA, Tang MB, Du P, Wang YH, Hu ZW, Xu YM, Schisler JC
(2018) PLoS Genet 14: e1007664
MeSH Terms: Animals, Behavior, Animal, CRISPR-Cas Systems, Cognition, Disease Models, Animal, Female, Humans, Male, Mice, Mice, Inbred C57BL, Models, Molecular, Motor Activity, Mutagenesis, Site-Directed, Phenotype, Point Mutation, Protein Domains, Protein Multimerization, Rats, Rats, Sprague-Dawley, Spinocerebellar Ataxias, Ubiquitin-Protein Ligases
Show Abstract · Added March 26, 2019
CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.
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Mutual activation of glutamatergic mGlu and muscarinic M receptors reverses schizophrenia-related changes in rodents.
Cieślik P, Woźniak M, Rook JM, Tantawy MN, Conn PJ, Acher F, Tokarski K, Kusek M, Pilc A, Wierońska JM
(2018) Psychopharmacology (Berl) 235: 2897-2913
MeSH Terms: Amphetamine, Animals, Antipsychotic Agents, Disease Models, Animal, Dizocilpine Maleate, Dose-Response Relationship, Drug, Excitatory Amino Acid Agonists, Male, Mice, Motor Activity, Phosphinic Acids, Receptor, Muscarinic M4, Receptors, Metabotropic Glutamate, Rodentia, Schizophrenia
Show Abstract · Added April 11, 2019
RATIONALE - Metabotropic glutamate receptors and muscarinic M receptors have been proposed as novel targets for various brain disorders, including schizophrenia. Both receptors are coupled to G proteins and are expressed in brain circuits that are important in schizophrenia. Therefore, their mutual activation may be an effective treatment and allow minimizing the doses of ligands required for optimal activity.
OBJECTIVES - In the present studies, subactive doses of mGlu and M activators (LSP4-2022 and VU152100, respectively) were administered to investigate the mutual interaction between mGlu and M receptors in animal models of schizophrenia.
METHODS - The behavioral tests used were MK-801-induced hyperactivity, (±)-2.5-dimethoxy-4-iodoamphetamine hydrochloride (DOI)-induced head twitches, the modified forced swim test, and MK-801-induced disruptions of social interactions and novel object recognition. DOI-induced spontaneous excitatory postsynaptic currents (sEPSCs) in brain slices and positron emission tomography (PET) in were used to establish the ability of these compounds to modulate the glutamatergic and dopaminergic systems. Rotarod was used to assess putative adverse effects.
RESULTS - The mutual administration of subactive doses of LSP4-2022 and VU152100 exerted similar antipsychotic-like efficacy in animals as observed for active doses of both compounds, indicating their additive actions. VU152100 inhibited the DOI-induced frequency (but not amplitude) of sEPSCs in the frontal cortex, confirming presynaptic regulation of glutamate release. Both compounds reversed amphetamine-induced decrease in D receptor levels in the striatum, as measured with [F]fallypride. The compounds did not induce any motor impartments when measured in rotarod test.
CONCLUSIONS - Based on our results, the simultaneous activation of M and mGlu receptors is beneficial in reversing MK-801- and amphetamine-induced schizophrenia-related changes in animals.
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Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward.
Reddy IA, Smith NK, Erreger K, Ghose D, Saunders C, Foster DJ, Turner B, Poe A, Albaugh VL, McGuinness O, Hackett TA, Grueter BA, Abumrad NN, Flynn CR, Galli A
(2018) PLoS Biol 16: e2006682
MeSH Terms: Animals, Bariatric Surgery, Behavior, Animal, Bile, Choice Behavior, Cocaine, Dopamine, Gallbladder, Ileum, Male, Mice, Inbred C57BL, Mice, Knockout, Motor Activity, Nucleus Accumbens, Reward, Signal Transduction
Show Abstract · Added January 4, 2019
The gut-to-brain axis exhibits significant control over motivated behavior. However, mechanisms supporting this communication are poorly understood. We reveal that a gut-based bariatric surgery chronically elevates systemic bile acids and attenuates cocaine-induced elevations in accumbal dopamine. Notably, this surgery reduces reward-related behavior and psychomotor sensitization to cocaine. Utilizing a knockout mouse model, we have determined that a main mediator of these post-operative effects is the Takeda G protein-coupled bile acid receptor (TGR5). Viral restoration of TGR5 in the nucleus accumbens of TGR5 knockout animals is sufficient to restore cocaine reward, centrally localizing this TGR5-mediated modulation. These findings define TGR5 and bile acid signaling as pharmacological targets for the treatment of cocaine abuse and reveal a novel mechanism of gut-to-brain communication.
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16 MeSH Terms
mGlu and mGlu modulate distinct excitatory inputs to the nucleus accumbens shell.
Turner BD, Rook JM, Lindsley CW, Conn PJ, Grueter BA
(2018) Neuropsychopharmacology 43: 2075-2082
MeSH Terms: Animals, Cocaine, Female, Mediodorsal Thalamic Nucleus, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neuronal Plasticity, Neurons, Nucleus Accumbens, Optogenetics, Oxazoles, Prefrontal Cortex, Pyridines, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate, Synapses, Synaptic Transmission
Show Abstract · Added March 3, 2020
Glutamatergic transmission in the nucleus accumbens shell (NAcSh) is a substrate for reward learning and motivation. Metabotropic glutamate (mGlu) receptors regulate NAcSh synaptic strength by inducing long-term depression (LTD). Inputs from prefrontal cortex (PFC) and medio-dorsal thalamus (MDT) drive opposing motivated behaviors yet mGlu receptor regulation of these synapses is unexplored. We examined Group I mGlu receptor regulation of PFC and MDT glutamatergic synapses onto specific populations of NAc medium spiny neurons (MSNs) using D1tdTom BAC transgenic mice and optogenetics. Synaptically evoked long-term depression (LTD) at MDT-NAcSh synapses required mGlu but not mGlu and was specific for D1(+) MSNs, whereas PFC LTD was expressed at both D1(+) and D1(-) MSNs and required mGlu but not mGlu. Two weeks after five daily non-contingent cocaine exposures (15 mg/kg), LTD was attenuated at MDT-D1(+) synapses but was rescued by the mGlu5-positive allosteric modulator (PAM) VU0409551. These results highlight unique plasticity mechanisms regulating specific NAcSh synapses.
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MeSH Terms
Reduced pupil dilation during action preparation in schizophrenia.
Thakkar KN, Brascamp JW, Ghermezi L, Fifer K, Schall JD, Park S
(2018) Int J Psychophysiol 128: 111-118
MeSH Terms: Adult, Executive Function, Female, Humans, Inhibition, Psychological, Male, Middle Aged, Motor Activity, Pupil, Saccades, Schizophrenia
Show Abstract · Added March 18, 2020
Impairments in cognitive control-the ability to exert control over thoughts and actions and respond flexibly to the environment-are well-documented in schizophrenia. However, the degree to which experimental task performance reflects true cognitive control impairments or more general alterations in effort, arousal and/or task preparedness is unclear. Pupillary responses can provide insight into these latter factors, as the pupil dilates with degree of cognitive effort and response preparation. In the current study, 16 medicated outpatients with schizophrenia (SZP) and 18 healthy controls performed a task that measures the ability to reactively inhibit and modify a planned action-the double-step task. In this task, participants were required to make a saccade to a visual target. Infrequently, the target jumped to a new location and participants were instructed to rapidly inhibit and change their eye movement plan. Applying a race model of performance, we have previously shown that SZP require more time to inhibit a planned action. In the current analysis, we measured pupil dilation associated with task preparation and found that SZP had a shallower increase in pupil size prior to the onset of the trial. Additionally, reduced magnitude of the pupil response was associated with negative symptom severity in patients. Based on primate neurophysiology and cognitive neuroscience work, we suggest that this blunted pupillary response may reflect abnormalities in a general orienting response or reduced motivational significance of a cue signifying the onset of a preparatory period and that these abnormalities might share an autonomic basis with negative symptoms.
Copyright © 2018 Elsevier B.V. All rights reserved.
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Reduced Nonexercise Activity Attenuates Negative Energy Balance in Mice Engaged in Voluntary Exercise.
Lark DS, Kwan JR, McClatchey PM, James MN, James FD, Lighton JRB, Lantier L, Wasserman DH
(2018) Diabetes 67: 831-840
MeSH Terms: Animals, Behavior, Animal, Calorimetry, Indirect, Energy Intake, Energy Metabolism, Male, Mice, Mice, Inbred C57BL, Motor Activity, Obesity, Physical Conditioning, Animal, Weight Loss
Show Abstract · Added March 26, 2019
Exercise alone is often ineffective for treating obesity despite the associated increase in metabolic requirements. Decreased nonexercise physical activity has been implicated in this resistance to weight loss, but the mechanisms responsible are unclear. We quantified the metabolic cost of nonexercise activity, or "off-wheel" activity (OWA), and voluntary wheel running (VWR) and examined whether changes in OWA during VWR altered energy balance in chow-fed C57BL/6J mice ( = 12). Energy expenditure (EE), energy intake, and behavior (VWR and OWA) were continuously monitored for 4 days with locked running wheels followed by 9 days with unlocked running wheels. Unlocking the running wheels increased EE as a function of VWR distance. The metabolic cost of exercise (kcal/m traveled) decreased with increasing VWR speed. Unlocking the wheel led to a negative energy balance but also decreased OWA, which was predicted to mitigate the expected change in energy balance by ∼45%. A novel behavioral circuit involved repeated bouts of VWR, and roaming was discovered and represented novel predictors of VWR behavior. The integrated analysis described here reveals that the weight loss effects of voluntary exercise can be countered by a reduction in nonexercise activity.
© 2018 by the American Diabetes Association.
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MeSH Terms
Mechanisms Associated With Physical Activity Behavior: Insights From Rodent Experiments.
Roberts MD, Ruegsegger GN, Brown JD, Booth FW
(2017) Exerc Sport Sci Rev 45: 217-222
MeSH Terms: Animals, Behavior, Animal, Dopaminergic Neurons, Motor Activity, Nucleus Accumbens, Rats, Signal Transduction
Show Abstract · Added October 23, 2017
Dopaminergic signaling differences in the nucleus accumbens (NAcc) seemingly predispose rats to adopt different physical activity behaviors. Physical activity behavior also may be regulated through peripheral mechanisms (i.e., muscle and fat derived as well as hormonal signals). We hypothesize that physical activity behavior is regulated by the convergence of central and peripheral mechanisms onto the NAcc.
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7 MeSH Terms
OCD candidate gene /EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.
Zike ID, Chohan MO, Kopelman JM, Krasnow EN, Flicker D, Nautiyal KM, Bubser M, Kellendonk C, Jones CK, Stanwood G, Tanaka KF, Moore H, Ahmari SE, Veenstra-VanderWeele J
(2017) Proc Natl Acad Sci U S A 114: 5719-5724
MeSH Terms: Amphetamines, Animals, Basal Ganglia, Cell Line, Central Nervous System Stimulants, Dopamine, Excitatory Amino Acid Transporter 3, Glutamic Acid, Grooming, Maze Learning, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Obsessive-Compulsive Disorder, Receptors, Dopamine D1, Reflex, Startle
Show Abstract · Added March 18, 2020
Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to , which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in () locomotor activity, () stereotypy, and () immediate early gene induction in the dorsal striatum following amphetamine administration. Further, -STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D receptor binding in the dorsal striatum of -STOP mice. -STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of /EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in -STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.
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M muscarinic activation induces long-lasting increase in intrinsic excitability of striatal projection neurons.
Lv X, Dickerson JW, Rook JM, Lindsley CW, Conn PJ, Xiang Z
(2017) Neuropharmacology 118: 209-222
MeSH Terms: Acetylcholine, Action Potentials, Animals, Channelrhodopsins, Choline O-Acetyltransferase, Cholinergic Agents, Corpus Striatum, Cues, Excitatory Amino Acid Antagonists, Excitatory Postsynaptic Potentials, Female, Gene Expression Regulation, Learning, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons, Photic Stimulation, Receptor, Muscarinic M1
Show Abstract · Added April 6, 2017
The dorsolateral striatum is critically involved in movement control and motor learning. Striatal function is regulated by a variety of neuromodulators including acetylcholine. Previous studies have shown that cholinergic activation excites striatal principal projection neurons, medium spiny neurons (MSNs), and this action is mediated by muscarinic acetylcholine subtype 1 receptors (M) through modulating multiple potassium channels. In the present study, we used electrophysiology techniques in conjunction with optogenetic and pharmacological tools to determine the long-term effects of striatal cholinergic activation on MSN intrinsic excitability. A transient increase in acetylcholine release in the striatum by optogenetic stimulation resulted in a long-lasting increase in excitability of MSNs, which was associated with hyperpolarizing shift of action potential threshold and decrease in afterhyperpolarization (AHP) amplitude, leading to an increase in probability of EPSP-action potential coupling. The M selective antagonist VU0255035 prevented, while the M selective positive allosteric modulator (PAM) VU0453595 potentiated the cholinergic activation-induced persistent increase in MSN intrinsic excitability, suggesting that M receptors are critically involved in the induction of this long-lasting response. This M receptor-dependent long-lasting change in MSN intrinsic excitability could have significant impact on striatal processing and might provide a novel mechanism underlying cholinergic regulation of the striatum-dependent motor learning and cognitive function. Consistent with this, behavioral studies indicate that potentiation of M receptor signaling by VU0453595 enhanced performance of mice in cue-dependent water-based T-maze, a dorsolateral striatum-dependent learning task.
Copyright © 2017. Published by Elsevier Ltd.
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21 MeSH Terms