scholarly journals Optogenetic Stimulation of Lateral Orbitofronto-Striatal Pathway Suppresses Compulsive Behaviors

Science ◽  
2013 ◽  
Vol 340 (6137) ◽  
pp. 1243-1246 ◽  
Author(s):  
Eric Burguière ◽  
Patrícia Monteiro ◽  
Guoping Feng ◽  
Ann M. Graybiel
Keyword(s):  
Response Inhibition ◽  
Behavioral Response ◽  
Repetitive Behavior ◽  
Projection Neuron ◽  
Repetitive Behaviors ◽  
Neuron Activity ◽  
Down Regulation ◽  
Delay Conditioning ◽  
Optogenetic Stimulation ◽  
Stimulation Of

Dysfunctions in frontostriatal brain circuits have been implicated in neuropsychiatric disorders, including those characterized by the presence of repetitive behaviors. We developed an optogenetic approach to block repetitive, compulsive behavior in a mouse model in which deletion of the synaptic scaffolding gene, Sapap3, results in excessive grooming. With a delay-conditioning task, we identified in the mutants a selective deficit in behavioral response inhibition and found this to be associated with defective down-regulation of striatal projection neuron activity. Focused optogenetic stimulation of the lateral orbitofrontal cortex and its terminals in the striatum restored the behavioral response inhibition, restored the defective down-regulation, and compensated for impaired fast-spiking neuron striatal microcircuits. These findings raise promising potential for the design of targeted therapy for disorders involving excessive repetitive behavior.

scholarly journals Optogenetic stimulation of the liver-projecting melanocortinergic pathway promotes hepatic glucose production

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Eunjin Kwon ◽  
Hye-Young Joung ◽  
Shun-Mei Liu ◽  
Streamson C. Chua ◽  
Gary J. Schwartz ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Receptor Gene ◽  
Critical Role ◽  
Neuron Activity ◽  
Motor Nucleus ◽  
Glucose Levels ◽  
Optogenetic Stimulation ◽  
Blood Glucose Levels ◽  
Melanocortin 4 Receptor Gene ◽  
Stimulation Of

AbstractThe central melanocortin system plays a fundamental role in the control of feeding and body weight. Proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (ARC) also regulate overall glucose homeostasis via insulin-dependent and -independent pathways. Here, we report that a subset of ARC POMC neurons innervate the liver via preganglionic parasympathetic acetylcholine (ACh) neurons in the dorsal motor nucleus of the vagus (DMV). Optogenetic stimulation of this liver-projecting melanocortinergic pathway elevates blood glucose levels that is associated with increased expression of hepatic gluconeogenic enzymes in female and male mice. Pharmacological blockade and knockdown of the melanocortin-4 receptor gene in the DMV abolish this stimulation-induced effect. Activation of melanocortin-4 receptors inhibits DMV cholinergic neurons and optogenetic inhibition of liver-projecting parasympathetic cholinergic fibers increases blood glucose levels. This elevated blood glucose is not due to altered pancreatic hormone release. Interestingly, insulin-induced hypoglycemia increases ARC POMC neuron activity. Hence, this liver-projecting melanocortinergic circuit that we identified may play a critical role in the counterregulatory response to hypoglycemia.

scholarly journals Familiality of behavioral flexibility and response inhibition deficits in autism spectrum disorder (ASD)

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Lauren M. Schmitt ◽  
Erin Bojanek ◽  
Stormi P. White ◽  
Michael E. Ragozzino ◽  
Edwin H. Cook ◽  
...  
Keyword(s):  
Autism Spectrum Disorder ◽  
Cognitive Control ◽  
Response Inhibition ◽  
Social Communication ◽  
Behavioral Response ◽  
Behavioral Flexibility ◽  
Autism Spectrum ◽  
Error Rates ◽  
Repetitive Behaviors ◽  
Spectrum Disorder

Abstract Background Diminished cognitive control, including reduced behavioral flexibility and behavioral response inhibition, has been repeatedly documented in autism spectrum disorder (ASD). We evaluated behavioral flexibility and response inhibition in probands and their parents using a family trio design to determine the extent to which these cognitive control impairments represent familial traits associated with ASD. Methods We examined 66 individuals with ASD (probands), 135 unaffected biological parents, and 76 typically developing controls. Participants completed a probabilistic reversal learning task (PRL) and a stop-signal task (SST) to assess behavioral flexibility and response inhibition respectively. Rates of PRL and SST errors were examined across groups, within families, and in relation to clinical and subclinical traits of ASD. Based on prior findings that subclinical broader autism phenotypic (BAP) traits may co-segregate within families and reflect heritable risk factors, we also examined whether cognitive control deficits were more prominent in families in which parents showed BAP features (BAP+). Results Probands and parents each showed increased rates of PRL and SST errors relative to controls. Error rates across tasks were not related. SST error rates inter-correlated among probands and their parents. PRL errors were more severe in BAP+ parents and their children relative to BAP− parents and their children. For probands of BAP+ parents, PRL and SST error rates were associated with more severe social-communication abnormalities and repetitive behaviors, respectively. Conclusion Reduced behavioral flexibility and response inhibition are present among probands and their unaffected parents, but represent unique familial deficits associated with ASD that track with separate clinical issues. Specifically, behavioral response inhibition impairments are familial in ASD and manifest independently from parental subclinical features. In contrast, behavioral flexibility deficits are selectively present in families with BAP characteristics, suggesting they co-segregate in families with parental subclinical social, communication, and rigid personality traits. Together, these findings provide evidence that behavioral flexibility and response inhibition impairments track differentially with ASD risk mechanisms and related behavioral traits.

scholarly journals Causal role for the subthalamic nucleus in interrupting behavior

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Kathryn H Fife ◽  
Navarre A Gutierrez-Reed ◽  
Vivien Zell ◽  
Julie Bailly ◽  
Christina M Lewis ◽  
...  
Keyword(s):  
Subthalamic Nucleus ◽  
Behavioral Response ◽  
Causal Role ◽  
Projection Neurons ◽  
Response Suppression ◽  
Disruptive Effect ◽  
Optogenetic Stimulation ◽  
Conflicting Information ◽  
Necessary And Sufficient ◽  
Stimulation Of

Stopping or pausing in response to threats, conflicting information, or surprise is fundamental to behavior. Evidence across species has shown that the subthalamic nucleus (STN) is activated by scenarios involving stopping or pausing, yet evidence that the STN causally implements stops or pauses is lacking. Here we used optogenetics to activate or inhibit mouse STN to test its putative causal role. We first demonstrated that optogenetic stimulation of the STN excited its major projection targets. Next we showed that brief activation of STN projection neurons was sufficient to interrupt or pause a self-initiated bout of licking. Finally, we developed an assay in which surprise was used to interrupt licking, and showed that STN inhibition reduced the disruptive effect of surprise. Thus STN activation interrupts behavior, and blocking the STN blunts the interruptive effect of surprise. These results provide strong evidence that the STN is both necessary and sufficient for such forms of behavioral response suppression.

scholarly journals Hunger neurons drive feeding through a sustained, positive reinforcement signal

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yiming Chen ◽  
Yen-Chu Lin ◽  
Christopher A Zimmerman ◽  
Rachel A Essner ◽  
Zachary A Knight
Keyword(s):  
Positive Reinforcement ◽  
Neural Mechanisms ◽  
Energy Deficit ◽  
Neuron Activity ◽  
Optogenetic Stimulation ◽  
Neuron Activation ◽  
Positive Valence ◽  
Stimulation Of ◽  
Hunger Drive

The neural mechanisms underlying hunger are poorly understood. AgRP neurons are activated by energy deficit and promote voracious food consumption, suggesting these cells may supply the fundamental hunger drive that motivates feeding. However recent in vivo recording experiments revealed that AgRP neurons are inhibited within seconds by the sensory detection of food, raising the question of how these cells can promote feeding at all. Here we resolve this paradox by showing that brief optogenetic stimulation of AgRP neurons before food availability promotes intense appetitive and consummatory behaviors that persist for tens of minutes in the absence of continued AgRP neuron activation. We show that these sustained behavioral responses are mediated by a long-lasting potentiation of the rewarding properties of food and that AgRP neuron activity is positively reinforcing. These findings reveal that hunger neurons drive feeding by transmitting a positive valence signal that triggers a stable transition between behavioral states.

scholarly journals Incerto-thalamic modulation of fear via GABA and dopamine

2021 ◽  
Author(s):  
Archana Venkataraman ◽  
Sarah C. Hunter ◽  
Maria Dhinojwala ◽  
Diana Ghebrezadik ◽  
JiDong Guo ◽  
...  
Keyword(s):  
Brain Regions ◽  
Zona Incerta ◽  
Dependent Manner ◽  
Post Traumatic Stress ◽  
Functional Roles ◽  
Functional Connections ◽  
Optogenetic Stimulation ◽  
Fear Generalization ◽  
Stimulation Of

AbstractFear generalization and deficits in extinction learning are debilitating dimensions of Post-Traumatic Stress Disorder (PTSD). Most understanding of the neurobiology underlying these dimensions comes from studies of cortical and limbic brain regions. While thalamic and subthalamic regions have been implicated in modulating fear, the potential for incerto-thalamic pathways to suppress fear generalization and rescue deficits in extinction recall remains unexplored. We first used patch-clamp electrophysiology to examine functional connections between the subthalamic zona incerta and thalamic reuniens (RE). Optogenetic stimulation of GABAergic ZI → RE cell terminals in vitro induced inhibitory post-synaptic currents (IPSCs) in the RE. We then combined high-intensity discriminative auditory fear conditioning with cell-type-specific and projection-specific optogenetics in mice to assess functional roles of GABAergic ZI → RE cell projections in modulating fear generalization and extinction recall. In addition, we used a similar approach to test the possibility of fear generalization and extinction recall being modulated by a smaller subset of GABAergic ZI → RE cells, the A13 dopaminergic cell population. Optogenetic stimulation of GABAergic ZI → RE cell terminals attenuated fear generalization and enhanced extinction recall. In contrast, optogenetic stimulation of dopaminergic ZI → RE cell terminals had no effect on fear generalization but enhanced extinction recall in a dopamine receptor D1-dependent manner. Our findings shed new light on the neuroanatomy and neurochemistry of ZI-located cells that contribute to adaptive fear by increasing the precision and extinction of learned associations. In so doing, these data reveal novel neuroanatomical substrates that could be therapeutically targeted for treatment of PTSD.

scholarly journals Imbalanced social-communicative and restricted repetitive behavior subtypes of autism spectrum disorder exhibit different neural circuitry

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Natasha Bertelsen ◽  
◽  
Isotta Landi ◽  
Richard A. I. Bethlehem ◽  
Jakob Seidlitz ◽  
...  
Keyword(s):  
Repetitive Behavior ◽  
Resting State Fmri ◽  
Neural Circuitry ◽  
Autism Spectrum ◽  
Repetitive Behaviors ◽  
Typically Developing ◽  
Out Of Sample ◽  
Genetic Mechanisms ◽  
Social Communicative ◽  
The Eu

AbstractSocial-communication (SC) and restricted repetitive behaviors (RRB) are autism diagnostic symptom domains. SC and RRB severity can markedly differ within and between individuals and may be underpinned by different neural circuitry and genetic mechanisms. Modeling SC-RRB balance could help identify how neural circuitry and genetic mechanisms map onto such phenotypic heterogeneity. Here, we developed a phenotypic stratification model that makes highly accurate (97–99%) out-of-sample SC = RRB, SC > RRB, and RRB > SC subtype predictions. Applying this model to resting state fMRI data from the EU-AIMS LEAP dataset (n = 509), we find that while the phenotypic subtypes share many commonalities in terms of intrinsic functional connectivity, they also show replicable differences within some networks compared to a typically-developing group (TD). Specifically, the somatomotor network is hypoconnected with perisylvian circuitry in SC > RRB and visual association circuitry in SC = RRB. The SC = RRB subtype show hyperconnectivity between medial motor and anterior salience circuitry. Genes that are highly expressed within these networks show a differential enrichment pattern with known autism-associated genes, indicating that such circuits are affected by differing autism-associated genomic mechanisms. These results suggest that SC-RRB imbalance subtypes share many commonalities, but also express subtle differences in functional neural circuitry and the genomic underpinnings behind such circuitry.

scholarly journals Involvement of MCH-oxytocin neural relay within the hypothalamus in murine nursing behavior

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yoko Kato ◽  
Harumi Katsumata ◽  
Ayumu Inutsuka ◽  
Akihiro Yamanaka ◽  
Tatsushi Onaka ◽  
...  
Keyword(s):  
Mammalian Species ◽  
Virgin Female ◽  
Essential Elements ◽  
Hypothalamic Nucleus ◽  
Male Mice ◽  
Hypothalamic Area ◽  
Functional Roles ◽  
Genetic Ablation ◽  
Optogenetic Stimulation ◽  
Stimulation Of

AbstractMultiple sequential actions, performed during parental behaviors, are essential elements of reproduction in mammalian species. We showed that neurons expressing melanin concentrating hormone (MCH) in the lateral hypothalamic area (LHA) are more active in rodents of both sexes when exhibiting parental nursing behavior. Genetic ablation of the LHA-MCH neurons impaired maternal nursing. The post-birth survival rate was lower in pups born to female mice with congenitally ablated MCH neurons under control of tet-off system, exhibiting reduced crouching behavior. Virgin female and male mice with ablated MCH neurons were less interested in pups and maternal care. Chemogenetic and optogenetic stimulation of LHA-MCH neurons induced parental nursing in virgin female and male mice. LHA-MCH GABAergic neurons project fibres to the paraventricular hypothalamic nucleus (PVN) neurons. Optogenetic stimulation of PVN induces nursing crouching behavior along with increasing plasma oxytocin levels. The hypothalamic MCH neural relays play important functional roles in parental nursing behavior in female and male mice.

scholarly journals Changes in Prefrontal Cortex–Thalamic Circuitry after Acoustic Trauma

Biomedicines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 77
Author(s):  
Kristin M. Barry ◽  
Donald Robertson ◽  
Wilhelmina H. A. M. Mulders
Keyword(s):  
Electrical Stimulation ◽  
Prefrontal Cortex ◽  
Auditory System ◽  
Acoustic Trauma ◽  
Neuron Activity ◽  
Compensatory Mechanism ◽  
Efferent Connections ◽  
Medial Geniculate ◽  
Central Auditory Pathways ◽  
Stimulation Of

In the adult auditory system, loss of input resulting from peripheral deafferentation is well known to lead to plasticity in the central nervous system, manifested as reorganization of cortical maps and altered activity throughout the central auditory pathways. The auditory system also has strong afferent and efferent connections with cortico-limbic circuitry including the prefrontal cortex and the question arises whether this circuitry is also affected by loss of peripheral input. Recent studies in our laboratory showed that PFC activation can modulate activity of the auditory thalamus or medial geniculate nucleus (MGN) in normal hearing rats. In addition, we have shown in rats that cochlear trauma resulted in altered spontaneous burst firing in MGN. However, whether the PFC influence on MGN is changed after cochlear trauma is unknown. We investigated the effects of electrical stimulation of PFC on single neuron activity in the MGN in anaesthetized Wistar rats 2 weeks after acoustic trauma or sham surgery. Electrical stimulation of PFC showed a variety of effects in MGN neurons both in sham and acoustic trauma groups but inhibitory responses were significantly larger in the acoustic trauma animals. These results suggest an alteration in functional connectivity between PFC and MGN after cochlear trauma. This change may be a compensatory mechanism increasing sensory gating after the development of altered spontaneous activity in MGN, to prevent altered activity reaching the cortex and conscious perception.

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