Anatomy, Physiology and Pharmacology
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Item Tyrosine Hydroxylase–Positive Nucleus Accumbens Neurons Influence Delay Discounting in a Mouse T-Maze Task(eNeuro, 2024-12) Appings, Ryan; Botterill, Justin J; Zhao, Mudi; Riaz, Sadia; Kanani, Asa; Violi, Francesca; Steininger Jr., Carl Frank David; Ito, Rutsuko; Arruda-Carvalho, MaitheDelay discounting (DD) is a phenomenon where individuals devalue a reward associated with a temporal delay, with the rate of devaluation being representative of impulsive-like behavior. Here, we first sought to develop and validate a mouse DD task to study brain circuits involved in DD decision-making within short developmental time windows, given widespread evidence of developmental regulation of impulse control and risk-taking. We optimized a T-maze DD task for mice that enables training and DD trials within 2 weeks. Mice learned to choose between a large and a small reward located at opposite arms of a T-maze. Once training criteria were met, mice underwent DD whereby the large reward choice was associated with a temporal delay. Task validation showed that adolescent C57BL/6J mice display an increased preference for the small reward upon a temporal delay, confirming increased impulsivity compared with adults. We next used this DD task to explore the neural basis of decision-making. We used tyrosine hydroxylase transgenic mice (TH-Cre) to target TH-positive neurons in the nucleus accumbens (NAc) and ventral tegmental area (VTA) with Cre-dependent excitatory or inhibitory designer receptors exclusively activated by designer drugs (DREADDs). Inhibition of transduced neurons in the NAc decreased preference for the small but immediate reward during DD. Inhibition of TH-positive neurons in the ventral tegmental area (VTA) did not affect impulsive choice in this DD task. These results uncover a novel role for NAc TH-positive neurons in DD behavior and expand the repertoire of behavioral tasks available for studying decision-making across the lifespan.Item Sex differences in exploratory behavior of rats successfully performing the object-in-place recognition memory test(Behavioural Brain Research, 2024-10) McElroy, Dan L.; Howland, JohnMale and female rodents display unique search strategies when exploring new and familiar environments. Sex differences are well-documented in the literature and may be observed in tasks that rely on spontaneous exploration (e.g., recognition memory tests). Therefore, we assessed patterns of male and female rat behavior in the object-in-place (OiP) test, a common recognition memory paradigm involving object-location associations. Twelve male and 12 female adult Long Evans rats were tested four times in the 1-h OiP test and exploratory behaviors were compared during habituation, sample, and test phases. Results revealed that females moved faster and farther than males, showed increased immobility frequency and reduced immobility duration, reduced outer zone mobility duration, and increased inner zone entrances, compared to males during habituations. During sample phases, female rats moved faster than males, displayed reduced immobility frequency in the inner zone, and demonstrated consistent distance travelled across repeated sessions; conversely, male rats moved less in later sessions and exhibited increased mobility frequency in the outer zone. Analyses comparing test phase behavior revealed females continued to move faster than males; however, no other sex differences were observed. These findings are consistent with previous literature highlighting unique sex differences in explorative behaviors during recognition testing. Sex differences in locomotion and mobility state behaviors may be more indicative of individual motivation and search strategy between the sexes and less indicative of recognition memory.Item Exosome-associated mitochondrial DNA in late-life depression: Implications for cognitive decline in older adults(Journal of Affective Disorders, 2024-06) Mendes-Silva, Ana Paula; Nikolova, Yuliya S.; Rajji, Tarek K.; Kennedy, James; Diniz, Breno; Gonçalves, Vanessa F.; Vieira, EricaBackground: Disrupted cellular communication, inflammatory responses and mitochondrial dysfunction are consistently observed in late-life depression (LLD). Exosomes (EXs) mediate cellular communication by transporting molecules, including mitochondrial DNA (EX-mtDNA), playing critical role in immunoregulation alongside tumor necrosis factor (TNF). Changes in EX-mtDNA are indicators of impaired mitochondrial function and might increase vulnerability to adverse health outcomes. Our study examined EX-mtDNA levels and integrity, exploring their associations with levels of TNF receptors I and II (TNFRI and TNFRII), and clinical outcomes in LLD. Methods: Ninety older adults (50 LLD and 40 controls (HC)) participated in the study. Blood was collected and exosomes were isolated using size-exclusion chromatography. DNA was extracted and EX-mtDNA levels and deletion were assessed using qPCR. Plasma TNFRI and TNFRII levels were quantified by multiplex immunoassay. Correlation analysis explored relationships between EX-mtDNA, clinical outcomes, and inflammatory markers. Results: Although no differences were observed in EX-mtDNA levels between groups, elevated levels correlated with poorer cognitive performance (r = − 0.328, p = 0.002) and increased TNFRII levels (r = 0.367, p = 0.004). LLD exhibited higher deletion rates (F(83,1) = 4.402, p = 0.039), with a trend remaining after adjusting for covariates (p = 0.084). Deletion correlated with poorer cognitive performance (r = − 0.335, p = 0.002). No other associations were found. Limitation: Cross-sectional study with a small number of participants from a specialized geriatric psychiatry treatment center. Conclusion: Our findings suggest that EX-mtDNA holds promise as an indicator of cognitive outcomes in LLD. Additional research is needed to further comprehend the role of EX-mtDNA levels/integrity in LLD, paving the way for its clinical application in the future.Item The T-type calcium channel antagonist, Z944, alters social behavior in Genetic Absence Epilepsy Rats from Strasbourg(2019) Marks, Wendie; Zabder, Nadine; Cain, Stuart; Snutch, Terrance; Howland, JohnItem Performance of the odour span task is not impaired following inactivations of parietal cortex in rats(2018) Scott, Gavin; Zabder, Nadine; Greba, Quentin; Howland, JohnItem Dissociable effects of the d- and l- enantiomers of govadine on the disruption of prepulse inhibition by MK-801 and apomorphine in male Long-Evans rats(2017) Lins, Brittney; Marks, Wendie; Phillips, Anthony; Howland, JohnItem Evidence for altered insulin signaling in the brains of Genetic Absence Epilepsy Rats from Strasbourg(2020) Sekar, Sathiya; Marks, Wendie; Gopalakrishnan, Venkat; Greba, Quentin; Snutch, Terrance; Howland, John; Taghibiglou, ChangizItem T-type calcium channels regulate the acquisition and recall of conditioned fear in male, Wistar rats(2020) Marks, Wendie; Zabder, Nadine; Snutch, Terrance; Howland, JohnItem NMDA receptors in visual and olfactory sensory integration in male Long Evans rats: a role for the orbitofrontal cortex(2020) Sandini, Thaisa; Marks, Wendie; Tahir, Nimra; Song, Yen; Greba, Quentin; Howland, JohnItem Effects of the metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on rats tested with the paired associates learning task in touchscreen-equipped operant conditioning chambers(Elsevier, 2016) Lins, Brittney; Howland, John G.Item The T-type calcium channel antagonist Z944 disrupts prepulse inhibition in both epileptic and non-epileptic rats(Elsevier, 2016) Marks, Wendie; Greba, Quentin; Cain, Stuart; Snutch, Terrance; Howland, John G.Item Performance of the trial-unique, delayed non-matching-to-location (TUNL) task depends on AMPA/Kainate, but not NMDA, ionotropic glutamate receptors in the rat posterior parietal cortex(Elsevier, 2019) Scott, Gavin; Roebuck, Andrew; Greba, Quentin; Howland, John G.Item Acute stress, but not corticosterone, facilitates acquisition of paired associates learning in rats using touchscreen-equipped operant conditioning chambers(Elsevier, 2018) Roebuck, Andrew; Liu, Max; Lins, Brittney; Scott, Gavin; Howland, John G.Item The T-type calcium channel antagonist, Z944, alters social behavior in Genetic Absence Epilepsy Rats from Strasbourg(Elsevier, 2019) Marks, Wendie; Zabder, Nadine; Cain, Stuart; Snutch, Terrance; Howland, John G.Item The Genetic Absence Epilepsy Rats from Strasbourg model of absence epilepsy exhibits alterations in fear conditioning and latent inhibition consistent with psychiatric comorbidities in humans(Wiley, 2016) Marks, Wendie; Cavanagh, Mary; Greba, Quentin; Cain, Stuart; Snutch, Terrance; Howland, John G.Item Sociability impairments in Genetic Absence Epilepsy Rats from Strasbourg: Reversal by the T-type calcium channel antagonist Z944(Elsevier, 2017) Henbid, Mark; Marks, Wendie; Collins, Madeline; Cain, Stuart; Snutch, Terrance; Howland, John G.Item The T-type calcium channel antagonist Z944 rescues impairments in crossmodal and visual recognition memory in Genetic Absence Epilepsy Rats from Strasbourg(Elsevier, 2016) Marks, Wendie; Cain, Stuart; Snutch, Terrance; Howland, John G.Item Maternal immune activation during pregnancy in rats impairs working memory capacity of the offspring(Elsevier, 2017) Murray, Brendan; Davies, Don; Molder, Joel; Howland, John G.Item Chronic maternal hyperglycemia induced during mid-pregnancy in rats increases RAGE expression, augments hippocampal excitability, and alters behavior of the offspring(Elsevier, 2015) Chandna, Andrew; Kuhlmann, Naila; Bryce, Courtney; Greba, Quentin; Campanucci, Veronica; Howland, John GItem Ventral hippocampal involvement in temporal order, but not recognition, memory for spatial information(Wiley, 2008) Howland, John; Harrison, Rebecca; Hannesson, Darren; Phillips, Anthony