- Email: [email protected]
500. Fronto-Striatal Modulation of Anxiety-Like Behaviors
Biological Psychiatry
Friday Abstracts
housed in SAP (19H light : 5H dark) for 2 weeks before FST, where they received scopolamine or mecamylamine. Results: Scopolamine (F(2,49)55.3, p,0.01) and mecamylamine (F(2,52)54.6, p,0.05) decreased FST immobility in mice pretreated with the physostigmine. Immobility was not decreased in mice pretreated with saline (F,1, ns). SAP increased immobility in two cohorts (F(1,70)56.5, p,0.05;F (1,143)54.3, p,0.05). In cohort 1, 0.03mg/kg scopolamine reduced immobility irrespective of photoperiod (F(1,70)56.9, p,0.05). As per our a priori hypotheses, it was discovered that this effect was driven by reduced immobility in the SAP (p,0.05), not in normal active photoperiod (NAP; 12:12) mice. In cohort 2, 0.56mg/kg mecamylamine slightly reduced immobility irrespective of photoperiod, but not significantly (F(1,143)52.0, p50.15). In combination, two ineffective doses of antagonist additively decreased FST immobility (F(3,142)53.0, p,0.05). Conclusions: These results support ACh neurotransmission in expression of depressive-like behaviors resulting from exposure to altered photoperiod. Future studies will use more direct manipulation of ACh in these conditions. Supported By: 5R01MH104344-03, 5T32MH018399-30 Keywords: Bipolar, Seasonal Affective Disorder, acetylcholine, Circadian Rhythms, Photoperiod
499. Disrupted Activity in Prefrontal Microcircuits in a Mouse Model of Genetic Risk for Psychiatric Illness Scott Wilke and Vikaas Sohal University of California, San Francisco Background: The prefrontal cortex (PFC) and the neurotransmitter dopamine have been centrally implicated in depression. In animal models, prefrontal neurons expressing dopamine D2 receptors (D2Rs) have reduced activity and regulate depression related behaviors. However, it is not known how genetic risk for developing depression influences the responses of prefrontal microcircuits to dopaminergic input. Methods: We have developed a novel assay, using live brain slices to image patterns of neural activity in isolated prefrontal microcircuits. A virus expressing the fluorescent activity reporter GCaMP6 was stereotactically targeted to medial PFC (mPFC) in mice. Subsequently, live slices were cut and activity imaged simultaneously from 70-100 prefrontal neurons during a baseline period and after exposure to a D2R agonist (quinpirole, 10 μM). Results: Mice expressing a truncated version of the human Disc1 gene are an established model of genetic risk for depression and psychosis. We find that in slices from control mice, mean network activity increases nearly 2-fold in response to D2R stimulation and this response is significantly blunted in Disc1 mutant slices. Using a cell-type specific approach we find that this effect is most prominent in a subcortically projecting deep layer network. We further find that the overall organization of network activity is disrupted in mutant mice, with a specific deficit in significant positive correlations between pairs of neurons. Conclusions: This novel assay defines an unbiased approach to discovering prefrontal microcircuit processes potentially important in the pathophysiology of depression and other psychiatric conditions.
Supported By: 3R01MH100292 - 04W1 NIMH R01 Supplement Keywords: Depression, Prefrontal Cortex, Dopamine, Microcircuits, calcium imaging
500. Fronto-Striatal Behaviors
Modulation
of
Anxiety-Like
Lisa Gunaydin1, Alexandra Nelson1, and Anatol Kreitzer2 University of California, San Francisco, 2Gladstone Institute of Neurological Disease
1
Background: Anxiety disorders are some of the most common mental illnesses. Existing pharmacological therapies do not help a substantial fraction of patients, however these disorders respond particularly well to cognitive therapy. The prefrontal cortex has long been implicated in cognitive control and anxiety-related behaviors, although the precise downstream circuits and cell types mediating prefrontal control of anxiety are poorly understood. Methods: Here we use a combination of in vivo and in vitro optogenetic and electrophysiological methods to identify causal top-down prefrontal projections and postsynaptic targets that control anxiety-like behavior in mice. Results: We found that optogenetic stimulation of medial prefrontal cortex (mPFC) projections to the dorsomedial striatum (DMS) had an anxiolytic effect in the elevated plus maze (n 5 9 Channelrhodopsin-2 (ChR2) and n 5 8 eYFP control animals; p 5 0.0003). In acute brain slices, mPFC projection stimulation preferentially recruited striatal medium spiny neurons (MSNs) expressing the D1 type dopamine receptor. Directly stimulating these postsynaptic D1 MSNs was sufficient to recapitulate the anxiolytic effect of mPFC-toDMS projection stimulation (n 5 12 ChR2 and n 5 20 control; p 5 0.002). Moreover, stimulating this fronto-striatal pathway was sufficient to rescue pathological behavior in a genetic mouse model of increased anxiety-like behavior. Conclusions: These results implicate a previously unexplored top-down pathway for anxiety control, and highlight a role for the DMS in modulating affective behavior in addition to its well-characterized role in motor and cognitive behaviors. Supported By: R01, UCSF Keywords: anxiety, obsessive-compulsive disorder, prefrontal cortex, striatum, optogenetics
501. Epigenetic Modifications of Stress-Relevant Genes as Peripheral Biomarkers of Treatment-Resistant Depression John Pfeiffer1, Angela Bustamante1, Joshua Price2, Susannah Tye2, and Monica Uddin3 University of Illinois at Urbana Champaign, 2Mayo Clinic, University of Illinois
1
3
Background: Mechanisms contributing to treatment resistant depression (TRD) are poorly understood. Identifying peripheral biomarkers will enhance mechanistic understanding of the disorder and establish targets for personalized treatment
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
S203
Friday Abstracts
housed in SAP (19H light : 5H dark) for 2 weeks before FST, where they received scopolamine or mecamylamine. Results: Scopolamine (F(2,49)55.3, p,0.01) and mecamylamine (F(2,52)54.6, p,0.05) decreased FST immobility in mice pretreated with the physostigmine. Immobility was not decreased in mice pretreated with saline (F,1, ns). SAP increased immobility in two cohorts (F(1,70)56.5, p,0.05;F (1,143)54.3, p,0.05). In cohort 1, 0.03mg/kg scopolamine reduced immobility irrespective of photoperiod (F(1,70)56.9, p,0.05). As per our a priori hypotheses, it was discovered that this effect was driven by reduced immobility in the SAP (p,0.05), not in normal active photoperiod (NAP; 12:12) mice. In cohort 2, 0.56mg/kg mecamylamine slightly reduced immobility irrespective of photoperiod, but not significantly (F(1,143)52.0, p50.15). In combination, two ineffective doses of antagonist additively decreased FST immobility (F(3,142)53.0, p,0.05). Conclusions: These results support ACh neurotransmission in expression of depressive-like behaviors resulting from exposure to altered photoperiod. Future studies will use more direct manipulation of ACh in these conditions. Supported By: 5R01MH104344-03, 5T32MH018399-30 Keywords: Bipolar, Seasonal Affective Disorder, acetylcholine, Circadian Rhythms, Photoperiod
499. Disrupted Activity in Prefrontal Microcircuits in a Mouse Model of Genetic Risk for Psychiatric Illness Scott Wilke and Vikaas Sohal University of California, San Francisco Background: The prefrontal cortex (PFC) and the neurotransmitter dopamine have been centrally implicated in depression. In animal models, prefrontal neurons expressing dopamine D2 receptors (D2Rs) have reduced activity and regulate depression related behaviors. However, it is not known how genetic risk for developing depression influences the responses of prefrontal microcircuits to dopaminergic input. Methods: We have developed a novel assay, using live brain slices to image patterns of neural activity in isolated prefrontal microcircuits. A virus expressing the fluorescent activity reporter GCaMP6 was stereotactically targeted to medial PFC (mPFC) in mice. Subsequently, live slices were cut and activity imaged simultaneously from 70-100 prefrontal neurons during a baseline period and after exposure to a D2R agonist (quinpirole, 10 μM). Results: Mice expressing a truncated version of the human Disc1 gene are an established model of genetic risk for depression and psychosis. We find that in slices from control mice, mean network activity increases nearly 2-fold in response to D2R stimulation and this response is significantly blunted in Disc1 mutant slices. Using a cell-type specific approach we find that this effect is most prominent in a subcortically projecting deep layer network. We further find that the overall organization of network activity is disrupted in mutant mice, with a specific deficit in significant positive correlations between pairs of neurons. Conclusions: This novel assay defines an unbiased approach to discovering prefrontal microcircuit processes potentially important in the pathophysiology of depression and other psychiatric conditions.
Supported By: 3R01MH100292 - 04W1 NIMH R01 Supplement Keywords: Depression, Prefrontal Cortex, Dopamine, Microcircuits, calcium imaging
500. Fronto-Striatal Behaviors
Modulation
of
Anxiety-Like
Lisa Gunaydin1, Alexandra Nelson1, and Anatol Kreitzer2 University of California, San Francisco, 2Gladstone Institute of Neurological Disease
1
Background: Anxiety disorders are some of the most common mental illnesses. Existing pharmacological therapies do not help a substantial fraction of patients, however these disorders respond particularly well to cognitive therapy. The prefrontal cortex has long been implicated in cognitive control and anxiety-related behaviors, although the precise downstream circuits and cell types mediating prefrontal control of anxiety are poorly understood. Methods: Here we use a combination of in vivo and in vitro optogenetic and electrophysiological methods to identify causal top-down prefrontal projections and postsynaptic targets that control anxiety-like behavior in mice. Results: We found that optogenetic stimulation of medial prefrontal cortex (mPFC) projections to the dorsomedial striatum (DMS) had an anxiolytic effect in the elevated plus maze (n 5 9 Channelrhodopsin-2 (ChR2) and n 5 8 eYFP control animals; p 5 0.0003). In acute brain slices, mPFC projection stimulation preferentially recruited striatal medium spiny neurons (MSNs) expressing the D1 type dopamine receptor. Directly stimulating these postsynaptic D1 MSNs was sufficient to recapitulate the anxiolytic effect of mPFC-toDMS projection stimulation (n 5 12 ChR2 and n 5 20 control; p 5 0.002). Moreover, stimulating this fronto-striatal pathway was sufficient to rescue pathological behavior in a genetic mouse model of increased anxiety-like behavior. Conclusions: These results implicate a previously unexplored top-down pathway for anxiety control, and highlight a role for the DMS in modulating affective behavior in addition to its well-characterized role in motor and cognitive behaviors. Supported By: R01, UCSF Keywords: anxiety, obsessive-compulsive disorder, prefrontal cortex, striatum, optogenetics
501. Epigenetic Modifications of Stress-Relevant Genes as Peripheral Biomarkers of Treatment-Resistant Depression John Pfeiffer1, Angela Bustamante1, Joshua Price2, Susannah Tye2, and Monica Uddin3 University of Illinois at Urbana Champaign, 2Mayo Clinic, University of Illinois
1
3
Background: Mechanisms contributing to treatment resistant depression (TRD) are poorly understood. Identifying peripheral biomarkers will enhance mechanistic understanding of the disorder and establish targets for personalized treatment
Biological Psychiatry May 15, 2017; 81:S140–S276 www.sobp.org/journal
S203