Inhibiting Rho kinase promotes goal-directed decision making and blocks habitual responding for cocaine

Swanson, Andrew M.; DePoy, Lauren M.; Gourley, Shannon L.

doi:10.1038/s41467-017-01915-4

Cited by 47 publications

(51 citation statements)

References 68 publications

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“…We used a task in which mice first learn to generate two food-reinforced nose pokes equivalently, then one behavior ceases to be reinforced, requiring mice to update expectancies and redirect responding. The PL is necessary for initially acquiring and consolidating information regarding action-outcome relationships (Ostlund and Balleine, 2005;Hart and Balleine, 2016;Swanson et al, 2017;Hart et al, 2018). The OFC is thought to build "task spaces" (Wilson et al, 2014;Stalnaker et al, 2015), essential to updating known associations.…”

Section: ␤1-integrins During a Critical Postnatal Period Support Ofc mentioning

confidence: 99%

β1-Integrins in the Developing Orbitofrontal Cortex Are Necessary for Expectancy Updating in Mice

et al. 2019

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Navigating a changing environment requires associating stimuli and actions with their likely outcomes and modifying these associations when they change. These processes involve the orbitofrontal cortex (OFC). Although some molecular mediators have been identified, developmental factors are virtually unknown. We hypothesized that the cell adhesion factor ␤1-integrin is essential to OFC function, anticipating developmental windows during which ␤1-integrins might be more influential than others. We discovered that OFC-selective ␤1-integrin silencing before adolescence, but not later, impaired the ability of mice to extinguish conditioned fear and select actions based on their likely outcomes. Early-life knock-down also reduced the densities of dendritic spines, the primary sites of excitatory plasticity in the brain, and weakened sensitivity to cortical inputs. Notwithstanding these defects in male mice, females were resilient to OFC (but not hippocampal) ␤1-integrin loss. Existing literature suggests that resilience may be explained by estradiol-mediated transactivation of ␤1-integrins and tropomyosin receptor kinase B (trkB). Accordingly, we discovered that a trkB agonist administered during adolescence corrected reward-related decision making in ␤1-integrin-deficient males. In sum, developmental ␤1-integrins are indispensable for OFC function later in life.

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Section: ␤1-integrins During a Critical Postnatal Period Support Ofc mentioning

confidence: 99%

β1-Integrins in the Developing Orbitofrontal Cortex Are Necessary for Expectancy Updating in Mice

et al. 2019

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“…For example, many forms of learning and memory are accompanied by dendritic spinogenesis (Moser et al, 1994;Leuner et al, 2003;Restivo et al, 2009;Vetere et al, 2011a,b;Bock et al, 2014;Kuhlman et al, 2014;Nishiyama, 2014;González-Tapia et al, 2015Mahmmoud et al, 2015;Jasinska et al, 2016;Ma et al, 2016) or spine elimination (Vetere et al, 2011b;Sanders et al, 2012;Jasinska et al, 2016;Ma et al, 2016;Swanson et al, 2017). Spine plasticity is also associated with proficiency of certain motor tasks (Fu et al, 2012;Liston et al, 2013;Hayashi-Takagi et al, 2015;Gonzalez-Tapia et al, 2016) and potentially, action-outcome expectation, given that drugs that enhance action-outcome learning can trigger spine elimination in certain brain regions (Swanson et al, 2017). Additional pharmacological investigations revealed that action-outcome-based decision-making was associated with dendritic spines containing large heads in the OFC (DePoy et al, 2016;Sharp et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Reward-Related Expectations Trigger Dendritic Spine Plasticity in the Mouse Ventrolateral Orbitofrontal Cortex

et al. 2019

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An essential aspect of goal-directed decision-making is selecting actions based on anticipated consequences, a process that involves the orbitofrontal cortex (OFC) and potentially, the plasticity of dendritic spines in this region. To investigate this possibility, we trained male and female mice to nose poke for food reinforcers, or we delivered the same number of food reinforcers non-contingently to separate mice. We then decreased the likelihood of reinforcement for trained mice, requiring them to modify action-outcome expectations. In a separate experiment, we blocked action-outcome updating via chemogenetic inactivation of the OFC. In both cases, successfully selecting actions based on their likely consequences was associated with fewer immature, thin-shaped dendritic spines and a greater proportion of mature, mushroom-shaped spines in the ventrolateral OFC. This pattern was distinct from spine loss associated with aging, and we identified no effects on hippocampal CA1 neurons. Given that the OFC is involved in prospective calculations of likely outcomes, even when they are not observable, constraining spinogenesis while preserving mature spines may be important for solidifying durable expectations. To investigate causal relationships, we inhibited the RNA-binding protein fragile X mental retardation protein (encoded by Fmr1), which constrains dendritic spine turnover. Ventrolateral OFC-selective Fmr1 knockdown recapitulated the behavioral effects of inducible OFC inactivation (and lesions; also shown here), impairing action-outcome conditioning, and caused dendritic spine excess. Our findings suggest that a proper balance of dendritic spine plasticity within the OFC is necessary for one's ability to select actions based on anticipated consequences.

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“…Despite these caveats, ROCK-based drug studies continue to extend the implications 77 of this treatment strategy for brain disorders as well as illuminate basic functions of the ROCKs. For instance, 78 recent findings indicate that directed delivery of Fasudil to the prefrontal cortex enhances goal-directed 79 behavior in mice and blocks habitual response for cocaine (DePoy et al, 2017; Swanson et al, 2017). 80…”

Section: Introduction 56mentioning

confidence: 99%

Distinct and Complementary Functions of Rho kinase isoforms ROCK1 and ROCK2 in Prefrontal Cortex Structural Plasticity

Greathouse

Boros

Deslauriers

et al. 2018

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Twenty-nine protein kinase inhibitors have been used to treat human diseases. Out of these, two are Rho-associated protein kinase (ROCK) 1 and 2 inhibitors. ROCKs are attractive drug targets for a range of neurologic disorders; however a critical barrier to ROCK-based therapeutics is ambiguity over whether there are isoform-specific roles for ROCKs in neuronal structural plasticity. Here, we used a genetics approach to address this long-standing question. Both male and female adult ROCK1+/− and ROCK2+/− mice exhibited anxiety-like behaviors compared to littermate controls. Individual pyramidal neurons in the medial prefrontal cortex (mPFC) were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and neuronal 3D reconstructions for morphometry analysis. Increased apical and basolateral dendritic length and intersections were observed in ROCK1+/− but not ROCK2+/− mice. Although dendritic spine densities were comparable among genotypes, apical spine extent was decreased in ROCK1+/− but increased in ROCK2+/− mice. Spine head and neck diameter were reduced similarly in ROCK1+/− and ROCK2+/− mice; however certain spine morphologic subclasses were more affected than others in a genotype-dependent manner. Biochemical analyses of ROCK substrates revealed that phosphorylation of LIM kinase was reduced in synaptic fractions from ROCK1+/− or ROCK2+/− mice, correlating to overlapping spine morphology phenotypes. Collectively, these observations implicate ROCK1 as a novel regulatory factor of neuronal dendritic structure and detail distinct and complementary roles of ROCKs in mPFC dendritic spine structural plasticity. This study provides a fundamental basis for current and future development of isoform-selective ROCK inhibitors to treat neurologic disorders.Significance StatementThe Rho-associated protein kinases (ROCK) 1 and 2 heavily influence neuronal architecture and synaptic plasticity. ROCKs are exciting drug targets and pan-ROCK inhibitors are clinically approved to treat hypertension, heart failure, glaucoma, spinal cord injury, and stroke. However development of isoform-specific ROCK inhibitors is hampered due to ambiguity over ROCK1- or ROCK2-specific functions in the brain. Our study begins to address this critical barrier and demonstrates that ROCK1 can mediate the dendritic arbor of neurons while both ROCK1 and ROCK2 heavily influence dendritic spine morphology. This study highlights distinct and complementary roles for ROCK1 and ROCK1 in prefrontal cortex structural plasticity and provides a fundamental basis for future development of isoform-selective ROCK inhibitors to treat neurologic disorders.

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Inhibiting Rho kinase promotes goal-directed decision making and blocks habitual responding for cocaine

Cited by 47 publications

References 68 publications

β1-Integrins in the Developing Orbitofrontal Cortex Are Necessary for Expectancy Updating in Mice

β1-Integrins in the Developing Orbitofrontal Cortex Are Necessary for Expectancy Updating in Mice

Reward-Related Expectations Trigger Dendritic Spine Plasticity in the Mouse Ventrolateral Orbitofrontal Cortex

Distinct and Complementary Functions of Rho kinase isoforms ROCK1 and ROCK2 in Prefrontal Cortex Structural Plasticity

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