RESUMO
Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity is associated with compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced grooming in Sapap3-knockouts. Together, these findings highlight the striatal indirect pathway as a potential treatment target for compulsive behavior.
Assuntos
Comportamento Compulsivo , Modelos Animais de Doenças , Fluoxetina , Asseio Animal , Camundongos Knockout , Neurônios , Transtorno Obsessivo-Compulsivo , Optogenética , Animais , Transtorno Obsessivo-Compulsivo/fisiopatologia , Transtorno Obsessivo-Compulsivo/genética , Comportamento Compulsivo/fisiopatologia , Camundongos , Neurônios/metabolismo , Asseio Animal/fisiologia , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Masculino , Corpo Estriado/metabolismo , Comportamento Animal , Camundongos Endogâmicos C57BL , Feminino , Vias NeuraisRESUMO
BACKGROUND: Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks. However, it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment. METHODS: Sapap3 knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3 KOs and control littermates were injected with a virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18 mg/kg, 4 weeks). RESULTS: Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. In addition, KOs displayed distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalized after fluoxetine. Finally, reversal learning-associated neurons were distributed randomly among grooming-associated neurons (i.e., overlap is what would be expected by chance). CONCLUSIONS: In OCD, LOFC is disrupted during both compulsive behaviors and reversal learning, but whether these behaviors share common neural underpinnings is unknown. We found that LOFC plays distinct roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.
Assuntos
Fluoxetina , Transtorno Obsessivo-Compulsivo , Camundongos , Animais , Fluoxetina/farmacologia , Reversão de Aprendizagem/fisiologia , Asseio Animal , Córtex Pré-Frontal , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Camundongos Knockout , Proteínas do Tecido Nervoso/fisiologiaRESUMO
RATIONALE: Elevated whole-blood serotonin (5-HT) is a robust biomarker in ~ 30% of patients with autism spectrum disorders, in which repetitive behavior is a core symptom. Furthermore, elevated whole-blood 5-HT has also been described in patients with pediatric obsessive-compulsive disorder. The 5-HT1B receptor is associated with repetitive behaviors seen in both disorders. Chronic blockade of serotonin transporter (SERT) reduces 5-HT1B receptor levels in the orbitofrontal cortex (OFC) and attenuates the sensorimotor deficits and hyperactivity seen with the 5-HT1B agonist RU24969. We hypothesized that enhanced SERT function would increase 5-HT1B receptor levels in OFC and enhance sensorimotor deficits and hyperactivity induced by RU24969. OBJECTIVES: We examined the impact of the SERT Ala56 mutation, which leads to enhanced SERT function, on 5-HT1B receptor binding and 5-HT1B-mediated sensorimotor deficits. METHODS: Specific binding to 5-HT1B receptors was measured in OFC and striatum of naïve SERT Ala56 or wild-type mice. The impact of the 5-HT1A/1B receptor agonist RU24969 on prepulse inhibition (PPI) of startle, hyperactivity, and expression of cFos was examined. RESULTS: While enhanced SERT function increased 5-HT1B receptor levels in OFC of Ala56 mice, RU24969-induced PPI deficits and hyperlocomotion were not different between genotypes. Baseline levels of cFos expression were not different between groups. RU24969 increased cFos expression in OFC of wild-types and decreased cFos in the striatum. CONCLUSIONS: While reducing 5-HT1B receptors may attenuate sensorimotor gating deficits, increased 5-HT1B levels in SERT Ala56 mice do not necessarily exacerbate these deficits, potentially due to compensations during neural circuit development in this model system.
Assuntos
Comportamento Animal/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/efeitos dos fármacos , Receptor 5-HT1B de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Substituição de Aminoácidos , Animais , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Genótipo , Hipercinese/genética , Hipercinese/psicologia , Indóis/farmacologia , Masculino , Camundongos , Mutação/genética , Inibição Pré-Pulso/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Filtro Sensorial/efeitos dos fármacos , Agonistas do Receptor 5-HT1 de Serotonina/farmacologiaRESUMO
The hippocampus is essential for the consolidation of some explicit long-term memories, including trace conditioning. Lesions and pharmacological manipulations of the dorsal hippocampus (DH) have provided strong evidence for its involvement in the acquisition and expression of trace fear memories. However, no studies have specifically targeted DH subregions [CA1 and dentate gyrus (DG)] to determine their involvement in trace fear conditioning. In the present study, rats received bilateral cannulation targeting either the DG or CA1 of the DH. Following surgery, animals were trace fear conditioned. Forty-eight hours following training, rats received bilateral infusions of the AMPA/kainate glutamate receptor antagonist, CNQX, or vehicle. Following the infusion, rats were placed in a novel context for the tone test. Rats that received CNQX into the DG froze significantly less during the tone and trace interval as compared to controls. Rats that received CNQX into the DH CA1 showed no difference in freezing during the tone or trace interval as compared to controls. These data support a role for the DG in the expression of trace tone fear conditioning.
Assuntos
6-Ciano-7-nitroquinoxalina-2,3-diona/farmacologia , Condicionamento Clássico/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Análise de Variância , Animais , Giro Denteado/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Masculino , Movimento (Física) , Ratos , Ratos Long-Evans , Fatores de TempoRESUMO
Previous work has shown that damage to the dorsal hippocampus (DH) occurring at recent, but not remote, timepoints following acquisition produces a deficit in trace conditioned fear memory expression. The opposite pattern has been observed with lesions to the medial prefrontal cortex (mPFC). The present studies address: (1) whether these lesion effects are observable within 30 d of training; (2) whether lesions of the ventral hippocampus (VH) produce temporally graded retrograde amnesia similar to DH lesions; and (3) whether the lesion-to-test interval critically contributes to these lesion deficits. In Experiment 1, excitotoxic lesions of the DH, VH, or mPFC were made at 1 or 30 d following trace fear conditioning. DH and VH lesioned animals showed a deficit in freezing to the tone at the recent, but not remote, timepoint. Medial PFC lesioned animals showed the opposite pattern. In Experiment 2, lesions to DH, VH, or mPFC were made 1 d following training, while testing occurred 30 d later. There were no deficits in freezing to the tone in any lesion condition compared to controls. These results suggest that systems consolidation of trace fear memory occurs within 30 d of acquisition, but does not depend on hippocampus-mPFC interactions during this period.
Assuntos
Hipocampo/fisiologia , Memória/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Condicionamento Clássico , Medo/fisiologia , Masculino , Ratos , Ratos Long-Evans , TempoRESUMO
The mouse has emerged as an advantageous species for studying the brain circuitry that underlies complex behavior and for modeling neuropsychiatric disease. The transition from flexible, goal-directed actions to inflexible, habitual responses is argued to be a valid and reliable behavioral model for studying a core aspect of corticostriatal systems that is implicated in certain forms of psychopathology. This transition is thought to correspond to a progression of behavioral control from associative to sensorimotor corticobasal ganglia networks. Habits form following extensive training and are characterized by reduced sensitivity of instrumental responding to reinforcer revaluation; few studies have examined this form of behavioral control in mice. Here we examined the involvement of the dorsolateral and dorsomedial striatum in this transition in the C57BL/6 inbred mouse strain. We provided evidence that damage to the dorsolateral striatum disrupted habitual responding, i.e. it preserved sensitivity to changes in outcome value following either outcome devaluation or, shown for the first time in mice, outcome inflation. Together, these data show that instrumental responding in lesioned mice tracks the current value of a reinforcer and provide evidence that neuroanatomical mechanisms underlying habit learning in rats are preserved in the mouse. This will allow for the genetic and molecular dissection of neural factors involved in decision-making and mechanisms of aberrant habit formation.