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Voluntary Exercise Boosts Striatal Dopamine Release: Evidence for the Necessary and Sufficient Role of BDNF

Bastioli, Guendalina; Arnold, Jennifer C; Mancini, Maria; Mar, Adam C; Gamallo-Lana, Begoña; Saadipour, Khalil; Chao, Moses V; Rice, Margaret E
Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in ex vivo corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted after a week of rest. We tested a role for BDNF in the influence of exercise on DA release using mice that were heterozygous for BDNF deletion (BDNF+/-). In contrast to WT mice, evoked DA release did not differ between BDNF+/- runners and controls. Complementary pharmacological studies using a tropomyosin receptor kinase B (TrkB) agonist in WT mouse slices showed that TrkB receptor activation also increased evoked DA release throughout striatum in an ACh-independent manner. Together, these data support a causal role for BDNF in exercise-enhanced striatal DA release and provide mechanistic insight into the beneficial effects of exercise in neuropsychiatric disorders, including Parkinson's, depression, and anxiety.SIGNIFICANCE STATEMENT Exercise has been shown to improve movement and cognition in humans and rodents. Here, we report that voluntary exercise for 30 d leads to an increase in evoked DA release throughout the striatum and an increase in BDNF in the dorsal (motor) striatum. The increase in DA release appears to require BDNF, indicated by the absence of DA release enhancement with running in BDNF+/- mice. Activation of BDNF receptors using a pharmacological agonist was also shown to boost DA release. Together, these data support a necessary and sufficient role for BDNF in exercise-enhanced DA release and provide mechanistic insight into the reported benefits of exercise in individuals with dopamine-linked neuropsychiatric disorders, including Parkinson's disease and depression.
PMID: 35577554
ISSN: 1529-2401
CID: 5277432

Oxytocin neurons enable social transmission of maternal behaviour

Carcea, Ioana; Caraballo, Naomi López; Marlin, Bianca J; Ooyama, Rumi; Riceberg, Justin S; Mendoza Navarro, Joyce M; Opendak, Maya; Diaz, Veronica E; Schuster, Luisa; Alvarado Torres, Maria I; Lethin, Harper; Ramos, Daniel; Minder, Jessica; Mendoza, Sebastian L; Bair-Marshall, Chloe J; Samadjopoulos, Grace H; Hidema, Shizu; Falkner, Annegret; Lin, Dayu; Mar, Adam; Wadghiri, Youssef Z; Nishimori, Katsuhiko; Kikusui, Takefumi; Mogi, Kazutaka; Sullivan, Regina M; Froemke, Robert C
Maternal care, including by non-biological parents, is important for offspring survival1-8. Oxytocin1,2,9-15, which is released by the hypothalamic paraventricular nucleus (PVN), is a critical maternal hormone. In mice, oxytocin enables neuroplasticity in the auditory cortex for maternal recognition of pup distress15. However, it is unclear how initial parental experience promotes hypothalamic signalling and cortical plasticity for reliable maternal care. Here we continuously monitored the behaviour of female virgin mice co-housed with an experienced mother and litter. This documentary approach was synchronized with neural recordings from the virgin PVN, including oxytocin neurons. These cells were activated as virgins were enlisted in maternal care by experienced mothers, who shepherded virgins into the nest and demonstrated pup retrieval. Virgins visually observed maternal retrieval, which activated PVN oxytocin neurons and promoted alloparenting. Thus rodents can acquire maternal behaviour by social transmission, providing a mechanism for adapting the brains of adult caregivers to infant needs via endogenous oxytocin.
PMID: 34381215
ISSN: 1476-4687
CID: 4972632

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice

Voisin, Maud; Shrestha, Elina; Rollet, Claire; Nikain, Cyrus A; Josefs, Tatjana; Mahé, Mélanie; Barrett, Tessa J; Chang, Hye Rim; Ruoff, Rachel; Schneider, Jeffrey A; Garabedian, Michela L; Zoumadakis, Chris; Yun, Chi; Badwan, Bara; Brown, Emily J; Mar, Adam C; Schneider, Robert J; Goldberg, Ira J; Pineda-Torra, Inés; Fisher, Edward A; Garabedian, Michael J
Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.
PMID: 33772096
ISSN: 2399-3642
CID: 4823692

Impulsivity is a heritable trait in rodents and associated with a novel quantitative trait locus on chromosome 1

Jupp, Bianca; Pitzoi, Silvia; Petretto, Enrico; Mar, Adam C; Oliver, Yolanda Pena; Jordan, Emily R; Taylor, Stephanie; Atanur, Santosh S; Srivastava, Prashant K; Saar, Kathrin; Hubner, Norbert; Sommer, Wolfgang H; Staehlin, Oliver; Spanagel, Rainer; Robinson, Emma S; Schumann, Gunter; Moreno, Margarita; Everitt, Barry J; Robbins, Trevor W; Aitman, Timothy J; Dalley, Jeffrey W
Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. Although a number of genes for impulsivity have been identified, no study to date has carried out an unbiased, genome-wide approach to identify genetic markers associated with impulsivity in experimental animals. Herein we report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait. Premature responding was found to be heritable (h2 = 13-16%), with significant linkage (LOD 5.2) identified on chromosome 1. Fine mapping of this locus identified a number of polymorphic candidate genes, however only one, beta haemoglobin, was differentially expressed in both the founder strain and F6 generation. These findings provide novel insights into the genetic substrates and putative neurobiological mechanisms of impulsivity with broader translational relevance for impulsivity-related disorders in humans.
PMID: 32317713
ISSN: 2045-2322
CID: 4397072

Dopamine D2-like receptor stimulation blocks negative feedback in visual and spatial reversal learning in the rat: behavioural and computational evidence

Alsiö, Johan; Phillips, Benjamin U; Sala-Bayo, Júlia; Nilsson, Simon R O; Calafat-Pla, Teresa C; Rizwand, Arazo; Plumbridge, Jessica M; López-Cruz, Laura; Dalley, Jeffrey W; Cardinal, Rudolf N; Mar, Adam C; Robbins, Trevor W
RATIONALE/BACKGROUND:Dopamine D2-like receptors (D2R) are important drug targets in schizophrenia and Parkinson's disease, but D2R ligands also cause cognitive inflexibility such as poor reversal learning. The specific role of D2R in reversal learning remains unclear. OBJECTIVES/OBJECTIVE:We tested the hypotheses that D2R agonism impairs reversal learning by blocking negative feedback and that antagonism of D1-like receptors (D1R) impairs learning from positive feedback. METHODS:Male Lister Hooded rats were trained on a novel visual reversal learning task. Performance on "probe trials", during which the correct or incorrect stimulus was presented with a third, probabilistically rewarded (50% of trials) and therefore intermediate stimulus, revealed individual learning curves for the processes of positive and negative feedback. The effects of D2R and D1R agonists and antagonists were evaluated. A separate cohort was tested on a spatial probabilistic reversal learning (PRL) task after D2R agonism. Computational reinforcement learning modelling was applied to choice data from the PRL task to evaluate the contribution of latent factors. RESULTS:D2R agonism with quinpirole dose-dependently impaired both visual reversal and PRL. Analysis of the probe trials on the visual task revealed a complete blockade of learning from negative feedback at the 0.25 mg/kg dose, while learning from positive feedback was intact. Estimated parameters from the model that best described the PRL choice data revealed a steep and selective decrease in learning rate from losses. D1R antagonism had a transient effect on the positive probe trials. CONCLUSIONS:D2R stimulation impairs reversal learning by blocking the impact of negative feedback.
PMID: 31218428
ISSN: 1432-2072
CID: 3939252

Divergent effects of AUTS2 in the cortex and cerebellumon ethanol preference and ataxia [Meeting Abstract]

Stafford, J M; Pelloux, Y; Lee, P; Gao, Z; Mar, A; Reinberg, D
Background and Purpose: An emerging role is beginning to be appreciated for the abnormal regulation of transcriptional programs in regulating alcohol use disorders (AUD) associated behaviors. We speculate that one such transcriptional regulator, AUTS2 plays a role in AUD-associated behaviors given links between Auts2/AUTS2 brain expression and SNPs with ethanol (EtOH) consumption in mice and human, respectively. Therefore, these studies sought to understand whether Auts2 contributes to AUD-associated behaviors and if so, what brain regions and chromatin dynamics are important in mitigating these behaviors Methods: Our studies relied on mice with a floxed Auts2 locus crossed to Cre-driver lines producing whole brain (Nestin-Cre), forebrain (EMX1-cre) or purkinje cell (PCP2-Cre) specific knockout of AUTS2 (AUTS2 cKO), respectively. All comparisons weremade between wild-type (WT) and heterozygous Auts2 cKO littermates (HET) on EtOH consumption behaviors (two-bottle choice, lickometer) and accelerating rotarod following EtOH challenge. Neural tissue was also harvested from select subgroups of cKO and subject to RNA-sequencing (RNA-Seq) to determine the brain-region specific consequences of AUTS2 deletion on the transcriptome.
Result(s): A critical finding of these studies was that AUTS2 affects EtOH preference in a brain region specific manner. Specifically, whole brain and forebrain AUTS2 cKO led to elevated EtOH preference relative to WTlittermates, while purkinje AUTS2 cKO had negligible effect on EtOH preference. In contrast, only the purkinje-AUTS2 cKO impacted performance on an accelerating rotarod following EtOH challenge whereas forebrain specific AUTS2 cKO did not. RNA-seq on the developing cortex and cerebellum further suggest unique transcriptional programs associated with AUTS2 cKO in those brain regions.
Conclusion(s): This work suggests that AUTS2 may play a key role in the propensity to consume EtOH as well as sensitivity to the locomotor properties of EtOH. Furthermore, the effects of AUTS2 on locomotor behavior appear to be rooted in the cerebellum while the consummatory behaviors may rely more on cortical circuits. The precise behavioral substrates, neural networks as well as the mechanisms by which AUTS2 drives transcriptional networks in discrete brain regions are continued areas of study. Together, the present studies suggest that AUTS2 may be key in regulating transcriptional programs that give rise to select AUD phenotypes
ISSN: 1530-0277
CID: 4024712

Chronic PD-1 Checkpoint Blockade Does Not Affect Cognition or Promote Tau Clearance in a Tauopathy Mouse Model

Lin, Yan; Rajamohamedsait, Hameetha B; Sandusky-Beltran, Leslie A; Gamallo-Lana, Begona; Mar, Adam; Sigurdsson, Einar M
Programmed cell death protein 1 (PD-1) checkpoint blockade with an antibody has been shown to reduce amyloid-β plaques, associated pathologies and cognitive impairment in mouse models. More recently, this approach has shown effectiveness in a tauopathy mouse model to improve cognition and reduce tau lesions. Follow-up studies by other laboratories did not see similar benefits of this type of therapy in other amyloid-β plaque models. Here, we report a modest increase in locomotor activity but no effect on cognition or tau pathology, in a different more commonly used tauopathy model following a weekly treatment for 12 weeks with the same PD-1 antibody and isotype control as in the original Aβ- and tau-targeting studies. These findings indicate that further research is needed before clinical trials based on PD-1 checkpoint immune blockage are devised for tauopathies.
PMID: 31992982
ISSN: 1663-4365
CID: 4294152

Continuous performance test impairment in a 22q11.2 microdeletion mouse model: improvement by amphetamine

Nilsson, Simon R O; Heath, Christopher J; Takillah, Samir; Didienne, Steve; Fejgin, Kim; Nielsen, Vibeke; Nielsen, Jacob; Saksida, Lisa M; Mariani, Jean; Faure, Philippe; Didriksen, Michael; Robbins, Trevor W; Bussey, Timothy J; Mar, Adam C
The 22q11.2 deletion syndrome (22q11.2DS) confers high risk of neurodevelopmental disorders such as schizophrenia and attention-deficit hyperactivity disorder. These disorders are associated with attentional impairment, the remediation of which is important for successful therapeutic intervention. We assessed a 22q11.2DS mouse model (Df(h22q11)/+) on a touchscreen rodent continuous performance test (rCPT) of attention and executive function that is analogous to human CPT procedures. Relative to wild-type littermates, Df(h22q11)/+ male mice showed impaired attentional performance as shown by decreased correct response ratio (hit rate) and a reduced ability to discriminate target stimuli from non-target stimuli (discrimination sensitivity, or d'). The Df(h22q11)/+ model exhibited decreased prefrontal cortical-hippocampal oscillatory synchrony within multiple frequency ranges during quiet wakefulness, which may represent a biomarker of cognitive dysfunction. The stimulant amphetamine (0-1.0 mg/kg, i.p.) dose-dependently improved d' in Df(h22q11)/+ mice whereas the highest dose of modafinil (40 mg/kg, i.p.) exacerbated their d' impairment. This is the first report to directly implicate attentional impairment in a 22q11.2DS mouse model, mirroring a key endophenotype of the human disorder. The capacity of the rCPT to detect performance impairments in the 22q11.2DS mouse model, and improvement following psychostimulant-treatment, highlights the utility and translational potential of the Df(h22q11)/+ model and this automated behavioral procedure.
PMID: 30429456
ISSN: 2158-3188
CID: 3457462

Effects of anterior cingulate cortex lesions on a continuous performance task for mice

Hvoslef-Eide, Martha; Nilsson, Simon Ro; Hailwood, Jonathan M; Robbins, Trevor W; Saksida, Lisa M; Mar, Adam C; Bussey, Timothy J
Important tools in the study of prefrontal cortical-dependent executive functions are cross-species behavioural tasks with translational validity. A widely used test of executive function and attention in humans is the continuous performance task (CPT). Optimal performance in variations of this task is associated with activity along the medial wall of the prefrontal cortex, including the anterior cingulate cortex (ACC), for its essential components such as response control, target detection and processing of false alarm errors. We assess the validity of a recently developed rodent touchscreen continuous performance task (rCPT) that is analogous to typical human CPT procedures. Here we evaluate the performance of mice with quinolinic acid-induced lesions centred on the ACC in the rCPT following a range of task parameter manipulations designed to challenge attention and impulse control. Lesioned mice showed a disinhibited response profile expressed as a decreased response criterion and increased false alarm rates. ACC lesions also resulted in a milder increase in inter-trial interval responses ('ITI touches') and hit rate. Lesions did not affect discriminative sensitivity d'. The disinhibited behaviour of ACC lesioned animals was stable and not affected by the manipulation of variable task parameter manipulations designed to increase task difficulty. The results are in general agreement with human studies implicating the ACC in the processing of inappropriate responses. We conclude that the rCPT may be useful for studying prefrontal cortex function in mice and has the capability of providing meaningful links between animal and human cognitive tasks.
PMID: 31168482
ISSN: 2398-2128
CID: 3917952

The anterior insula bidirectionally modulates cost-benefit decision making on a rodent gambling task

Daniel, M L; Cocker, P J; Lacoste, J; Mar, A C; Houeto, J L; Belin-Rauscent, A; Belin, D
Deficits in cost-benefit decision making, as assessed in the Iowa Gambling Task (IGT), are commonly observed in neuropsychiatric disorders such as addiction. There is considerable variation in the maximisation of rewards on such tasks, both in the general population and in rodent models, suggesting individual differences in decision making may represent a key endophenotype for vulnerability to neuropsychiatric disorders. Increasing evidence suggests that the insular cortex, which is involved in interoception and emotional processes in humans, may be a key neural locus in the control of decision making processes. However, the extent to which the insula contributes to individual differences in cost-benefit decision making remains unknown. Using male Sprague-Dawley rats we first assessed individual differences in the performance over the course of a single session on a rodent analogue of the IGT (rGT). Rats were matched for their ability to maximise reward and received bilateral excitotoxic or sham lesions of the anterior insula cortex (AIC). Animals were subsequently challenged on a second rGT session with altered contingencies. Finally, animals were also assessed for instrumental conditioning and reversal learning. AIC lesions produced bidirectional alterations on rGT performance; rats that had performed optimally prior to surgery subsequently showed impairments, and animals that had performed poorly showed improvements in comparison to sham operated controls. These bidirectional effects were not attributable to alterations in behavioural flexibility or in motivation. These data suggest that the recruitment of the AIC during decision making may be state-dependent and help guide response selection toward subjectively favourable options.
PMID: 28887899
ISSN: 1460-9568
CID: 2688452