Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

Ahmari, Susanne E.; Spellman, Timothy; Douglass, Neria L.; Kheirbek, Mazen A.; Simpson, Helen Blair; Deisseroth, Karl; Gordon, Joshua A.; Hen, René

doi:10.1126/science.1234733

Cited by 438 publications

(413 citation statements)

References 42 publications

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“…Grooming is considered a displacement behavior to attenuate the appetitive response (forage) in the absence of the stimulus (food). When manifested in excess, grooming has also been related to obsessive-compulsive behaviors in mice (Ahmari et al, 2013;Burguière et al, 2013), similar to digging (Karvat and Kimchi, 2012). Thus, our findings indicate that, in addition to appetitive and consummatory aspects of hunger, the activation of Agrp neurons in AgrpTrpv1 mice is sufficient to drive repetitive/stereotypic behaviors, an unsuspected role for these hypothalamic neurons.…”

Section: Repertoire Of Home-cage Behaviorsmentioning

confidence: 59%

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Dietrich¹,

Zimmer²,

Bober³

et al. 2017

Cell

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SUMMARYThe nervous system evolved to coordinate flexible goal-directed behaviors by integrating interoceptive and sensory information. Hypothalamic Agrp neurons are known to be crucial for feeding behavior. Here, however, we show that these neurons also orchestrate other complex behaviors in adult mice. Activation of Agrp neurons in the absence of food triggers foraging and repetitive behaviors, which are reverted by food consumption. These stereotypic behaviors that are triggered by Agrp neurons are coupled with decreased anxiety. NPY 5 receptor signaling is necessary to mediate the repetitive behaviors after Agrp neuron activation while having minor effects on feeding. Thus, we have unmasked a functional role for Agrp neurons in controlling repetitive behaviors mediated, at least in part, by neuropeptidergic signaling. The findings reveal a new set of behaviors coupled to the energy homeostasis circuit and suggest potential therapeutic avenues for diseases with stereotypic behaviors.

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Section: Repertoire Of Home-cage Behaviorsmentioning

confidence: 59%

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Dietrich¹,

Zimmer²,

Bober³

et al. 2017

Cell

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“…Repeated corticostriatal activation generates persistent obsessive-compulsive disorder-like behavior [49]. Activation of corticalNAc core inputs promotes compulsive alcohol intake in mice [50].…”

Section: Discussionmentioning

confidence: 99%

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Yan

Cheng

et al. 2016

Neurosci. Bull.

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Abnormal approach-avoidance behavior has been linked to deficits in the mesolimbic dopamine (DA) system of the brain. Recently, increasing evidence has indicated that toll-like receptor 4 (TLR4), an important pattern-recognition receptor in the innate immune system, can be directly activated by substances of abuse, resulting in an increase of the extracellular DA level in the nucleus accumbens. We thus hypothesized that TLR4-dependent signaling might regulate approach-avoidance behavior. To test this hypothesis, we compared the novelty-seeking and social interaction behaviors of TLR4-deficient (TLR4 -/-) and wild-type (WT) mice in an approach-avoidance conflict situation in which the positive motivation to explore a novel object or interact with an unfamiliar mouse was counteracted by the negative motivation to hide in exposed, large spaces. We found that TLR4 -/-mice exhibited reduced novelty-seeking and social interaction in the large open spaces. In less stressful test apparatuses similar in size to the mouse cage, however, TLR4 -/-mice performed normally in both novelty-seeking and social interaction tests. The reduced exploratory behaviors under approachavoidance conflict were not due to a high anxiety level or an enhanced fear response in the TLR4 -/-mice, as these mice showed normal anxiety and fear responses in the open field and passive avoidance tests, respectively. Importantly, the novelty-seeking behavior in the large open field induced a higher level of c-Fos activation in the nucleus accumbens shell (NAcSh) in TLR4 -/-mice than in WT mice. Partially inactivating the NAcSh via infusion of GABA receptor agonists restored the novelty-seeking behavior of TLR4 -/-mice. These data suggested that TLR4 is crucial for positive motivational behavior under approach-avoidance conflict. TLR4-dependent activation of neurons in the NAcSh may contribute to this phenomenon.

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“…These actions of M 4 PAMs could also contribute to the ability of M 4 PAMs to reduce age-related progression of HD-associated physiological alterations. Nonetheless, the increase in corticostriatal transmission could contribute to alterations of both glutamatergic (43) and dopaminergic (44) synaptic transmission. Moreover, loss of striatal DA activity seen in symptomatic animals has been associated with aberrant plasticity (45), alterations of dendritic spines, and also alteration of glutamatergic signaling (46,47).…”

Section: Discussionmentioning

confidence: 99%

Allosteric activation of M ₄ muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

Pancani

Foster

Moehle

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Mutations that lead to Huntington's disease (HD) result in increased transmission at glutamatergic corticostriatal synapses at early presymptomatic stages that have been postulated to set the stage for pathological changes and symptoms that are observed at later ages. Based on this, pharmacological interventions that reverse excessive corticostriatal transmission may provide a novel approach for reducing early physiological changes and motor symptoms observed in HD. We report that activation of the M 4 subtype of muscarinic acetylcholine receptor reduces transmission at corticostriatal synapses and that this effect is dramatically enhanced in presymptomatic YAC128 HD and BACHD relative to wild-type mice. Furthermore, chronic administration of a novel highly selective M 4 positive allosteric modulator (PAM) beginning at presymptomatic ages improves motor and synaptic deficits in 5-mo-old YAC128 mice. These data raise the exciting possibility that selective M 4 PAMs could provide a therapeutic strategy for the treatment of HD.neurodegenerative | basal ganglia | movement disorder | trinucleotide repeat disorder H untington's disease (HD) is a rare and fatal neurodegenerative disease caused by an expansion of a CAG triplet repeat in Htt, the gene that encodes for the protein huntingtin (1, 2). HD is characterized by a prediagnostic phase that includes subtle changes in personality, cognition, and motor function, followed by a more severe symptomatic stage initially characterized by hyperkinesia (chorea), motor incoordination, deterioration of cognitive abilities, and psychiatric symptoms. At later stages of disease progression, patients experience dystonia, rigidity, and bradykinesia, and ultimately death (3-7). The cortex and striatum are the most severely affected brain regions in HD and, interestingly, an increasing number of reports suggest that alterations in cortical and striatal physiology are present in prediagnostic individuals and in young HD mice (6-16).Striatal spiny projection neurons (SPNs) receive large glutamatergic inputs from the cortex and thalamus, as well as dopaminergic innervation from the substantia nigra. In the healthy striatum, the interplay of these neurotransmitters coordinates the activity of SPNs and striatal interneurons, regulating motor planning and execution as well as cognition and motivation (17, 18). Htt mutations lead to an early increase in striatal glutamatergic transmission, which begins during the asymptomatic phase of HD (12-14) and could contribute to synaptic changes observed in later stages of HD (19,20). Based on this, pharmacological agents that reduce excitatory transmission in the striatum could reduce or prevent the progression of alterations in striatal synaptic function and behavior observed in symptomatic stages of HD.Muscarinic acetylcholine receptors (mAChRs), particularly M 4 , can inhibit transmission at corticostriatal synapses (21-25). Therefore, it is possible that selective activation of specific mAChR subtypes could normalize excessive corticostriatal t...

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Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

Cited by 438 publications

References 42 publications

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Allosteric activation of M ₄ muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

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Repeated Cortico-Striatal Stimulation Generates Persistent OCD-Like Behavior

Cited by 438 publications

References 42 publications

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Hypothalamic Agrp Neurons Drive Stereotypic Behaviors beyond Feeding

Toll-Like Receptor 4 Deficiency Causes Reduced Exploratory Behavior in Mice Under Approach-Avoidance Conflict

Allosteric activation of M 4 muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice

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Allosteric activation of M ₄ muscarinic receptors improve behavioral and physiological alterations in early symptomatic YAC128 mice