Increased perivascular space volume in white matter and basal ganglia is associated with cognition in Parkinson's Disease.

Perivascular spaces (PVS), fluid-filled compartments surrounding brain vasculature, are an essential component of the glymphatic system responsible for transport of waste and nutrients. Glymphatic system impairment may underlie cognitive deficits in Parkinson's disease (PD). Studies have focused on the role of basal ganglia PVS with cognition in PD, but the role of white matter PVS is unknown. This study examined the relationship of white matter and basal ganglia PVS with domain-specific and global cognition in individuals with PD. Fifty individuals with PD underwent 3T T1w magnetic resonance imaging (MRI) to determine PVS volume fraction, defined as PVS volume normalized to total regional volume, within (i) centrum semiovale, (ii) prefrontal white matter (medial orbitofrontal, rostral middle frontal, superior frontal), and (iii) basal ganglia. A neuropsychological battery included assessment of global cognitive function (Montreal Cognitive Assessment, and global cognitive composite score), and cognitive-specific domains (executive function, memory, visuospatial function, attention, and language). Higher white matter rostral middle frontal PVS was associated with lower scores in both global cognitive and visuospatial function. In the basal ganglia higher PVS was associated with lower scores for memory with a trend towards lower global cognitive composite score. While previous reports have shown that greater amount of PVS in the basal ganglia is associated with decline in global cognition in PD, our findings suggest that increased white matter PVS volume may also underlie changes in cognition.

Exercise alters cortico-basal ganglia network metabolic connectivity: a mesoscopic level analysis informed by anatomic parcellation defined in the mouse brain connectome.

The basal ganglia are important modulators of the cognitive and motor benefits of exercise. However, the neural networks underlying these benefits remain poorly understood. Our study systematically analyzed exercise-associated changes in metabolic connectivity in the cortico-basal ganglia-thalamic network during the performance of a new motor task, with regions-of-interest defined based on mesoscopic domains recently defined in the mouse brain structural connectome. Mice were trained on a motorized treadmill for six weeks or remained sedentary (control), thereafter undergoing [14C]-2-deoxyglucose metabolic brain mapping during wheel walking. Regional cerebral glucose uptake (rCGU) was analyzed in 3-dimensional brains reconstructed from autoradiographic brain sections using statistical parametric mapping. Metabolic connectivity was assessed by calculating inter-regional correlation of rCGU cross-sectionally across subjects within a group. Compared to controls, exercised animals showed broad decreases in rCGU in motor areas, but increases in limbic areas, as well as the visual and association cortices. In addition, exercised animals showed (i) increased positive metabolic connectivity within and between the motor cortex and caudoputamen (CP), (ii) newly emerged negative connectivity of the substantia nigra pars reticulata with the globus pallidus externus, and CP, and (iii) reduced connectivity of the prefrontal cortex (PFC). Increased metabolic connectivity in the motor circuit in the absence of increases in rCGU strongly suggests greater network efficiency, which is also supported by the reduced involvement of PFC-mediated cognitive control during the performance of a new motor task. Our study delineates exercise-associated changes in functional circuitry at the subregional level and provides a framework for understanding the effects of exercise on functions of the cortico-basal ganglia-thalamic network.

A mind in motion: Exercise improves cognitive flexibility, impulsivity and alters dopamine receptor gene expression in a Parkinsonian rat model.

Cognitive impairment, particularly deficits in executive function (EF) is common in Parkinson's disease (PD) and may lead to dementia. There are currently no effective treatments for cognitive impairment. Work from our lab and others has shown that physical exercise may improve motor performance in PD but its role in cognitive function remains poorly eludicated. In this study in a rodent model of PD, we sought to examine whether exercise improves cognitive processing and flexibility, important features of EF. Rats received 6-hydroxydopamine lesions of the bilateral striatum (caudate-putamen, CPu), specifically the dorsomedial CPu, a brain region central to EF. Rats were exercised on motorized running wheels or horizontal treadmills for 6-12 weeks. EF-related behaviors including attention and processing, as well as flexibility (inhibition) were evaluated using either an operant 3-choice serial reaction time task (3-CSRT) with rule reversal (3-CSRT-R), or a T-maze task with reversal. Changes in striatal transcript expression of dopamine receptors (Drd1-4) and synaptic proteins (Synaptophysin, PSD-95) were separately examined following 4 weeks of exercise in a subset of rats. Exercise/Lesion rats showed a modest, yet significant improvement in processing-related response accuracy in the 3-CSRT-R and T-maze, as well as a significant improvement in cognitive flexibility as assessed by inhibitory aptitude in the 3-CSRT-R. By four weeks, exercise also elicited increased expression of Drd1, Drd3, Drd4, synaptophysin, and PSD-95 in the dorsomedial and dorsolateral CPu. Our results underscore the observation that exercise, in addition to improving motor function may benefit cognitive performance, specifically EF, and that early changes (by 4 weeks) in CPu dopamine modulation and synaptic connectivity may underlie these benefits.

Physical activity intensity is associated with cognition and functional connectivity in Parkinson's disease.

BACKGROUND: Cognitive impairment is common in Parkinson's disease (PD) and often leads to dementia, with no effective treatment. Aging studies suggest that physical activity (PA) intensity has a positive impact on cognition and enhanced functional connectivity may underlie these benefits. However, less is known in PD. This cross-sectional study examined the relationship between PA intensity, cognitive performance, and resting state functional connectivity in PD and whether PA intensity influences the relationship between functional connectivity and cognitive performance. METHODS: 96 individuals with mild-moderate PD completed a comprehensive neuropsychological battery. Intensity of PA was objectively captured over a seven-day period using a wearable device (ActiGraph). Time spent in light and moderate intensity PA was determined based on standardized actigraphy cut points. Resting-state fMRI was assessed in a subset of 50 individuals to examine brain-wide functional connectivity. RESULTS: Moderate intensity PA (MIPA), but not light PA, was associated with better global cognition, visuospatial function, memory, and executive function. Individuals who met the WHO recommendation of ≥150 min/week of MIPA demonstrated better global cognition, executive function, and visuospatial function. Resting-state functional connectivity associated with MIPA included a combination of brainstem, hippocampus, and regions in the frontal, cingulate, and parietal cortices, which showed higher connectivity across the brain in those achieving the WHO MIPA recommendation. Meeting this recommendation positively moderated the associations between identified functional connectivity and global cognition, visuospatial function, and language. CONCLUSION: Encouraging MIPA, particularly the WHO recommendation of ≥150 min of MIPA/week, may represent an important prescription for PD cognition.

A gut-derived metabolite alters brain activity and anxiety behaviour in mice.

Integration of sensory and molecular inputs from the environment shapes animal behaviour. A major site of exposure to environmental molecules is the gastrointestinal tract, in which dietary components are chemically transformed by the microbiota1 and gut-derived metabolites are disseminated to all organs, including the brain2. In mice, the gut microbiota impacts behaviour3, modulates neurotransmitter production in the gut and brain4,5, and influences brain development and myelination patterns6,7. The mechanisms that mediate the gut-brain interactions remain poorly defined, although they broadly involve humoral or neuronal connections. We previously reported that the levels of the microbial metabolite 4-ethylphenyl sulfate (4EPS) were increased in a mouse model of atypical neurodevelopment8. Here we identified biosynthetic genes from the gut microbiome that mediate the conversion of dietary tyrosine to 4-ethylphenol (4EP), and bioengineered gut bacteria to selectively produce 4EPS in mice. 4EPS entered the brain and was associated with changes in region-specific activity and functional connectivity. Gene expression signatures revealed altered oligodendrocyte function in the brain, and 4EPS impaired oligodendrocyte maturation in mice and decreased oligodendrocyte-neuron interactions in ex vivo brain cultures. Mice colonized with 4EP-producing bacteria exhibited reduced myelination of neuronal axons. Altered myelination dynamics in the brain have been associated with behavioural outcomes7,9-14. Accordingly, we observed that mice exposed to 4EPS displayed anxiety-like behaviours, and pharmacological treatments that promote oligodendrocyte differentiation prevented the behavioural effects of 4EPS. These findings reveal that a gut-derived molecule influences complex behaviours in mice through effects on oligodendrocyte function and myelin patterning in the brain.

The Effects of Cardiorespiratory and Motor Skill Fitness on Intrinsic Functional Connectivity of Neural Networks in Individuals with Parkinson's Disease.

BACKGROUND: Studies in aging older adults have shown the positive association between cognition and exercise related fitness, particularly cardiorespiratory fitness. These reports have also demonstrated the association of high cardiorespiratory fitness, as well as other types of fitness, on the reversal of age-related decline in neural network connectivity, highlighting the potential role of fitness on age- and disease-related brain changes. While the clinical benefits of exercise are well-documented in Parkinson's disease (PD), the extent to which cardiorespiratory fitness (assessed by estimated VO2max testing) or motor skill fitness (assessed by the Physical Performance Test (PPT)) affects neural network connectivity in PD remains to be investigated. The purpose of this study was to explore the hypothesis that higher fitness level is associated with an increase in the intrinsic network connectivity of cognitive networks commonly affected in PD. METHODS: In this cross-sectional resting state fMRI, we used a multivariate statistical approach based on high-dimensional independent component analysis (ICA) to investigate the association between two independent fitness metrics (estimated VO2max and PPT) and resting state network connectivity. RESULTS: We found that increased estimated VO2max was associated with increased within network connectivity in cognitive networks known to be impaired in PD, including those sub-serving memory and executive function. There was a similar trend for high levels of PPT to be associated with increased within network connectivity in distinct resting state networks. The between functional network connectivity analysis revealed that cardiorespiratory fitness was associated with increased functional connectivity between somatosensory motor network and several cognitive networks sub-serving memory, attention, and executive function. CONCLUSION: This study provides important empirical data supporting the potential association between two forms of fitness and multiple resting state networks impacting PD cognition. Linking fitness to circuit specific modulation of resting state network connectivity will help establish a neural basis for the positive effects of fitness and specific exercise modalities and provide a foundation to identify underlying mechanisms to promote repair.

Thalamic volume mediates associations between cardiorespiratory fitness (VO2max) and cognition in Parkinson's disease.

INTRODUCTION: Cognitive deficits occur in Parkinson's disease (PD). Cardiorespiratory fitness (CRF) is associated with better cognitive performance in aging especially in executive function (EF) and memory. The association between CRF and cognitive performance is understudied in people with PD. Brain structures underlying associations also remains unknown. This cross-sectional study examined the associations between CRF and cognitive performance in PD. We also examined associations between CRF and brain structures impacted in PD. Mediation analysis were conducted to examine whether brain structures impacted in PD mediate putative associations between CRF and cognitive performance. METHODS: Individuals with PD (N = 33) underwent magnetic resonance imaging (MRI), CRF evaluation (estimated VO2max), and neuropsychological assessment. Composite cognitive scores of episodic memory, EF, attention, language, and visuospatial functioning were generated. Structural equation models were constructed to examine whether MRI volume estimates (thalamus and pallidum) mediated associations between CRF and cognitive performance (adjusting for age, education, PD disease duration, sex, MDS-UPDRS motor score, and total intracranial volume). RESULTS: Higher CRF was associated with better episodic memory (Standardized ß = 0.391; p = 0.008), EF (Standardized ß = 0.324; p = 0.025), and visuospatial performance (Standardized ß = 0.570; p = 0.005). Higher CRF was associated with larger thalamic (Standardized ß = 0.722; p = 0.004) and pallidum (Standardized ß = 0.635; p = 0.004) volumes. Thalamic volume mediated the association between higher CRF and better EF (Indirect effect = 0.309) and episodic memory (Indirect effect = 0.209) performance (p < 0.05). The pallidum did not significantly mediate associations between CRF and cognitive outcomes. CONCLUSION: The thalamus plays an important role in the association between CRF and both EF and episodic memory in PD.

Cognitive flexibility deficits in rats with dorsomedial striatal 6-hydroxydopamine lesions tested using a three-choice serial reaction time task with reversal learning.

Lesions of the dorsomedial striatum elicit deficits in cognitive flexibility that are an early feature of Parkinson's disease (PD), and presumably reflect alterations in frontostriatal processing. The current study aimed to examine deficits in cognitive flexibility in rats with bilateral 6-hydroxydopamine lesions in the dorsomedial striatum. While deficits in cognitive flexibility have previously been examined in rodent PD models using the cross-maze, T-maze, and a food-digging task, the current study is the first to examine such deficits using a 3-choice serial reaction time task (3-CSRT) with reversal learning (3-CSRT-R). Although the rate of acquisition in 3-CSRT was slower in lesioned compared to control rats, lesioned animals were able to acquire a level of accuracy comparable to that of control animals following 4 weeks of training. In contrast, substantial and persistent deficits were apparent during the reversal learning phase. Our results demonstrate that deficits in cognitive flexibility can be robustly unmasked by reversal learning in the 3-CSRT-R paradigm, which can be a useful test for evaluating effects of dorsomedial striatal deafferentation and interventions.

Modulation of Hippocampal GABAergic Neurotransmission and Gephyrin Levels by Dihydromyricetin Improves Anxiety.

Anxiety disorders are the most common mental illness in the U.S. and are estimated to consume one-third of the country's mental health spending. Although anxiolytic therapies are available, many patients exhibit treatment-resistance, relapse, or substantial side effects. An urgent need exists to explore the underlying mechanisms of chronic anxiety and to develop alternative therapies. Presently, we identified dihydromyricetin (DHM), a flavonoid that has anxiolytic properties in a mouse model of isolation-induced anxiety. Socially isolated mice demonstrated increased anxiety levels and reduced exploratory behavior measured by elevated plus-maze and open-field tests. Socially isolated mice showed impaired GABAergic neurotransmission, including reduction in GABAA receptor-mediated extrasynaptic tonic currents, as well as amplitude and frequency of miniature inhibitory postsynaptic currents measured by whole-cell patch-clamp recordings from hippocampal slices. Furthermore, intracellular ATP levels and gephyrin expression decreased in anxious animals. DHM treatment restored ATP and gephyrin expression, GABAergic transmission and synaptic function, as well as decreased anxiety-like behavior. Our findings indicate broader roles for DHM in anxiolysis, GABAergic neurotransmission, and synaptic function. Collectively, our data suggest that reduction in intracellular ATP and gephyrin contribute to the development of anxiety, and represent novel treatment targets. DHM is a potential candidate for pharmacotherapy for anxiety disorders.

Ceftriaxone inhibits stress-induced bladder hyperalgesia and alters cerebral micturition and nociceptive circuits in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study.

AIMS: Emotional stress plays a role in the exacerbation and development of interstitial cystitis/bladder pain syndrome (IC/BPS). Given the significant overlap of brain circuits involved in stress, anxiety, and micturition, and the documented role of glutamate in their regulation, we examined the effects of an increase in glutamate transport on central amplification of stress-induced bladder hyperalgesia, a core feature of IC/BPS. METHODS: Wistar-Kyoto rats were exposed to water avoidance stress (WAS, 1 hour/day x 10 days) or sham stress, with subgroups receiving daily administration of ceftriaxone (CTX), an activator of glutamate transport. Thereafter, cystometrograms were obtained during bladder infusion with visceromotor responses (VMR) recorded simultaneously. Cerebral blood flow (CBF) mapping was performed by intravenous injection of [14 C]-iodoantipyrine during passive bladder distension. Regional CBF was quantified in autoradiographs of brain slices and analyzed in three dimensional reconstructed brains with statistical parametric mapping. RESULTS: WAS elicited visceral hypersensitivity during bladder filling as demonstrated by a decreased pressure threshold and VMR threshold triggering the voiding phase. Brain maps revealed stress effects in regions noted to be responsive to bladder filling. CTX diminished visceral hypersensitivity and attenuated many stress-related cerebral activations within the supraspinal micturition circuit and in overlapping limbic and nociceptive regions, including the posterior midline cortex (posterior cingulate/anterior retrosplenium), somatosensory cortex, and anterior thalamus. CONCLUSIONS: CTX diminished bladder hyspersensitivity and attenuated regions of the brain that contribute to nociceptive and micturition circuits, show stress effects, and have been reported to demonstrated altered functionality in patients with IC/BPS. Glutamatergic pharmacologic strategies modulating stress-related bladder dysfunction may be a novel approach to the treatment of IC/BPS.

Voluntary exercise improves voiding function and bladder hyperalgesia in an animal model of stress-induced visceral hypersensitivity: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome research network study.

OBJECTIVE: The underlying mechanism of interstitial cystitis/bladder pain syndrome (IC/BPS) is not well understood and evaluation of current therapeutic interventions has not identified any generally effective treatments. Physical activity has shown beneficial effects on individuals suffering from chronic pain. Anxiety-prone rats exposed to water avoidance stress (WAS) develop urinary frequency and lower bladder sensory thresholds with high face and construct validity for the study of IC/BPS. The aim of this study was to evaluate the role of chronic voluntary exercise on urinary frequency, voiding function, and hyperalgesia in animals exposed to WAS. MATERIALS AND METHODS: Twenty-six female Wistar-Kyoto rats were exposed to WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Before euthanasia, the animals underwent cystometrogram (CMG), external urinary sphincter electromyography, and assessment of visceromotor response (VMR) to isotonic bladder distension (IBD). RESULTS: WAS exposure resulted in adverse changes in voiding parameters. Compared with sedentary animals, animals in the voluntary exercise group had improved voiding parameters during metabolic cage and CMG testing, as well as improved bladder sensory thresholds as determined by VMR during IBD. CONCLUSION: Voluntary exercise in an animal model of chronic stress leads to improvement in voiding function and visceral bladder hyperalgesia.

Exercise modulates neuronal activation in the micturition circuit of chronically stressed rats: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

BACKGROUND: Rats exposed to water avoidance stress (WAS) show increased urinary frequency, increased somatosensory nociceptive reflex responses, as well as altered brain responses to bladder distension, analogous to similar observations made in patients with urologic chronic pelvic pain syndrome (UCPPS). Exercise has been proposed as a potential treatment option for patients with chronic urinary frequency and urgency. We examined the effects of exercise on urinary voiding parameters and functional brain activation during bladder distension in rats exposed to WAS. METHODS: Adult, female Wistar Kyoto rats were exposed to 10 days of WAS and thereafter randomized to either voluntary exercise for 3 weeks or sedentary groups. Voiding parameters were assessed at baseline, post-WAS, and weekly for 3 weeks. Thereafter, cerebral blood flow (CBF) mapping was performed during isotonic bladder distension (20 cm H2O) after intravenous bolus injection of [14C]-iodoantipyrine. Regional CBF was quantified in autoradiographs of brain slices and analyzed in 3-D reconstructed brains by statistical parametric mapping. Functional connectivity was examined between regions of the micturition circuit through interregional correlation analysis. RESULTS: WAS exposure in sedentary animals (WAS/no-EX) increased voiding frequency and decreased urinary volumes per void. Exercise exposure in WAS animals (WAS/EX) resulted in a progressive decline in voiding frequency back to the baseline, as well as increased urinary volumes per void. Within the micturition circuit, WAS/EX compared to WAS/no-EX demonstrated a significantly lower rCBF response to passive bladder distension in Barrington's nucleus that is part of the spinobulbospinal voiding reflex, as well as in the periaqueductal gray (PAG) which modulates this reflex. Greater rCBF was noted in WAS/EX animals broadly across corticolimbic structures, including the cingulate, medial prefrontal cortex (prelimbic, infralimbic areas), insula, amygdala, and hypothalamus, which provide a 'top-down' decision point where micturition could be inhibited or triggered. WAS/EX showed a significantly greater positive brain functional connectivities compared to WAS/no-EX animals within regions of the extended reflex loop (PAG, Barrington's nucleus, intermediodorsal thalamic nucleus, pons), as well as within regions of the corticolimbic decision-making loop of the micturition circuit, with a strikingly negative correlation between these pathways. Urinary frequency was positively correlated with rCBF in the pons, and negatively correlated with rCBF in the cingulate cortex. CONCLUSION: Our results suggest that chronic voluntary exercise may decrease urinary frequency at two points of control in the micturition circuit. During the urine storage phase, it may diminish the influence of the reflex micturition circuit itself, and/or it may increase corticolimbic control of voiding. Exercise may be an effective adjunct therapeutic intervention for modifying the urinary symptoms in patients with UCPPS.

Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone.

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.

Sex differences in insular functional connectivity in response to noxious visceral stimulation in rats.

Insular cortex (INS) plays a critical role in pain processing and shows sex differences in functional activation during noxious visceral stimulation. Less is known regarding functional interactions within the INS and between this structure and other parts of the brain. Cerebral blood flow mapping was performed using [14C]-iodoantipyrine perfusion autoradiography in male and female rats during colorectal distension (CRD) or no distension (controls). Forty regions of interest (ROIs) were defined anatomically to represent the granular, dysgranular, and agranular INS along the anterior-posterior (A-P) axis. Inter-ROI correlation matrices were calculated for each group to characterize intra-insular functional connectivity (FC). Results showed a clear FC segregation within the INS into an anterior (rostral to bregma +2.4 mm), a posterior (caudal to bregma -1.2 mm), and a mid INS subregion in between. Female controls showed higher FC density compared to males. During CRD, intra-insular FC density decreased greatly in females, but only modestly in males, with a loss of long-range connections between the anterior and mid INS noted in both sexes. New functional organization was characterized in both sexes by a cluster in the mid INS and primarily short-range FC along the A-P axis. Seed correlation analysis during CRD showed sex differences in FC of the anterior and mid agranular INS with the medial prefrontal cortex, thalamus, and brainstem areas (periaqueductal gray, parabrachial nucleus), suggesting sex differences in the modulatory aspect of visceral pain processing. Our findings suggest presence of substantial sex differences in visceral pain processing at the level of the insula.

Positive Allosteric Modulation of Cholinergic Receptors Improves Spatial Learning after Cortical Contusion Injury in Mice.

We examined benzyl quinolone carboxylic acid (BQCA), a novel M1 muscarinic-positive allosteric modulator, for improving memory and motor dysfunction after cerebral cortical contusion injury (CCI). Adult mice received unilateral motorsensory cortical CCI or sham injury. Benzyl quinolone carboxylic acid (BQCA; 5, 10, and 20 mg/kg, intraperitoneally [i.p.] × 2/day × 3-4 weeks) or vehicle (Veh) were administered, and weekly evaluations were undertaken using a battery of motor tests, as well as the Morris water maze. Thereafter, cerebral metabolic activation was investigated in awake animals during walking with [14C]-2-deoxygIucose autoradiography, comparing CCI mice previously treated with BQCA (20 mg/kg) or vehicle. Relative changes in local cerebral glucose uptake (rCGU) were evaluated in three-dimensional-reconstructed brains using statistical parametric mapping. CCI resulted in mild hyperactivity in the open field, and modest significant motor deficits, as well as significantly decreased spatial learning at 3 weeks. BQCA in CCI mice resulted in significantly improved spatial recall during the third week, with minimal effects on motor outcomes. CCI significantly decreased rCGU in the ipsilesional basal ganglia-thalamocortical circuit and in somatosensory regions, with relative increases noted contralaterally, as well as in the cerebellum. Significant decreases in rCGU were noted in subregions of the ipsilesional hippocampal formation, with significant increases noted contralesionally. BQCA compared to vehicle-treated mice showed modest, though significantly increased, rCGU in motor regions, as well as a partial reversal of lesion-related rCGU findings in subregions of the hippocampal formation. rCGU in ipsilesional posterior CA1 demonstrated a significant inverse correlation with latency to find the submerged platform. BQCA at 20 mg/kg had no significant effect on general motor activity, body weight, or acute motor, secretory, or respiratory symptoms. Results suggest that BQCA is a candidate compound to improve learning and memory function after brain trauma and may not suffer the associated central nervous system side effects typically associated with even modest doses of other cholinergic enhancers.

Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study.

Stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitive syndromes, such as interstitial cystitis/bladder pain syndrome (IC/BPS), characterized by urinary frequency and bladder hyperalgesia and heightened stress responsiveness. Given the overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function, as well as its effects on regional brain activation during bladder filling. Female Wistar-Kyoto rats were exposed to WAS (10 days) or sham paradigms. One day thereafter, cystometrograms were obtained during titrated bladder dilation, with visceromotor responses (VMR) recorded simultaneously. Cerebral perfusion was assessed during passive bladder distension (20-cmH2O) following intravenous administration of [14C]-iodoantipyrine. Regional cerebral blood flow was quantified by autoradiography and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. WAS animals compared to controls demonstrated a decreased pressure threshold and visceromotor threshold triggering the voiding phase. At 20-cmH2O, VMR was significantly greater in WAS animals compared to controls. WAS animals showed greater activation in cortical regions of the central micturition circuit, including the posterior cingulate, anterior retrosplenial, somatosensory, posterior insula, orbital, and anterior secondary ("supplementary") motor cortices, as well as in the thalamus, anterior hypothalamus, parabrachial and Barrington nuclei, and striatum. Seed analysis showed increased functional connectivity of WAS compared to control animals of the posterior cingulate cortex to the pontine parabrachial nucleus; of the Barrington nucleus to the anterior dorsal midline and ventrobasilar thalamus and somatosensory and retrosplenial cortices; and of the posterior insula to anterior secondary motor cortex. Our findings show a visceral hypersensitivity during bladder filling in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency, viscerosensory perception and its relay to motor regions coordinating imminent bladder contraction. Results are consistent with recent findings in patients with interstitial cystitis, suggesting that WAS may serve as an animal model to elucidate the mechanisms leading to viscerosensitive brain phenotypes in humans with IC/BPS.

Recruitment of prefrontal-striatal circuit in response to skilled motor challenge.

A variety of physical fitness regimens have been shown to improve cognition, including executive function, yet our understanding of which parameters of motor training are important in optimizing outcomes remains limited. We used functional brain mapping to compare the ability of two motor challenges to acutely recruit the prefrontal-striatal circuit. The two motor tasks - walking in a complex running wheel with irregularly spaced rungs or walking in a running wheel with a smooth internal surface - differed only in the extent of skill required for their execution. Cerebral perfusion was mapped in rats by intravenous injection of [C]-iodoantipyrine during walking in either a motorized complex wheel or in a simple wheel. Regional cerebral blood flow (rCBF) was quantified by whole-brain autoradiography and analyzed in three-dimensional reconstructed brains by statistical parametric mapping and seed-based functional connectivity. Skilled or simple walking compared with rest, increased rCBF in regions of the motor circuit, somatosensory and visual cortex, as well as the hippocampus. Significantly greater rCBF increases were noted during skilled walking than for simple walking. Skilled walking, unlike simple walking or the resting condition, was associated with a significant positive functional connectivity in the prefrontal-striatal circuit (prelimbic cortex-dorsomedial striatum) and greater negative functional connectivity in the prefrontal-hippocampal circuit. Our findings suggest that the level of skill of a motor training task determines the extent of functional recruitment of the prefrontal-corticostriatal circuit, with implications for a new approach in neurorehabilitation that uses circuit-specific neuroplasticity to improve motor and cognitive functions.

Measurement of Cardiac Output and Blood Volume During Hemodialysis with Fluorescent Dye Dilution Technique.

Intradialytic hypotensive events (IDH) accompanied by deleterious decreases of the cardiac output complicate up to 25% of hemodialysis treatments. Monitoring options available to track hemodynamic changes during hemodialysis have been found ineffective to anticipate the occurrence of IDH. We have assembled opto-electronic instrumentation that uses the fluorescence of a small bolus of indocyanine green dye injected in the hemodialysis circuit to estimate cardiac output and blood volume based on indicator dilution principles in patients receiving hemodialysis. The instrument and technique were tested in 24 adult end-stage renal failure subjects during 64 hemodialysis sessions. A single calibration factor could be used across subjects and across time. Intra-subject variability of the measurements over time was <10%. Stroke volume index (SVI) (mean ± SEM = 34 ± 1 vs. 39 ± 2 mL m-2) and central blood volume (CBV) index (783 ± 36 vs. 881 ± 33 mL m-2) were lower at the beginning of the sessions in which IDH eventually occurred. Cardiac index, SVI, and CBV index decreased with hemodialysis in all treatment sessions but the decrease was more intense in the IDH sessions. We conclude that hemodynamic monitoring can be implemented in patients receiving hemodialysis with minimal disruption of the treatment and could help understand intradialytic hypotension.

Evidence of functional brain reorganization on the basis of blood flow changes in the CAG140 knock-in mouse model of Huntington's disease.

Neuroimaging, especially functional brain mapping, may provide insights into the distributed involvement of multiple brain regions and loops in disorders classically associated with pathology of a localized region. One example is Huntington's disease (HD), typically classified as a basal ganglia disorder. Here, we report genotypic differences in cerebral perfusion mapping in an HD mouse model characterized by a gene knock-in (KI) of a human exon 1 CAG140 expansion repeat (CAG140 KI mice). Animals were examined at 6 months and compared with wild-type littermates. Regional cerebral blood flow (rCBF) was mapped in the awake, nonrestrained, male mouse at rest using [C]-iodoantipyrine autoradiography and analyzed in three-dimensionally reconstructed brains by statistical parametric mapping. Our results showed significant changes in rCBF between CAG140 KI and WT mice, such that CAG140 KI animals showed hypoperfusion of the basal ganglia motor circuit and hyperperfusion of cerebellar-thalamic and somatosensory regions. Significant hypoperfusion was also noted in CAG140 KI mice in the prelimbic and cingulate cortex (medial prefrontal area) and the hippocampus - areas associated with cognitive processing and mood. Changes in rCBF were apparent in the absence of motor deficits (rotarod test) or atrophy in the striatum (caudate-putamen) or hemispheric volume. Our results suggest a functional reorganization of whole-brain networks at a presymptomatic stage in the life of the CAG140 KI mouse. Functional brain mapping in animals may, in the future, serve as a translational biomarker for identifying sites of early synaptic change in the HD brain and for directing targeted preclinical molecular studies and clinical therapies.

Engaging cognitive circuits to promote motor recovery in degenerative disorders. exercise as a learning modality.

Exercise and physical activity are fundamental components of a lifestyle essential in maintaining a healthy brain. This is primarily due to the fact that the adult brain maintains a high degree of plasticity and activity is essential for homeostasis throughout life. Plasticity is not lost even in the context of a neurodegenerative disorder, but could be maladaptive thus promoting disease onset and progression. A major breakthrough in treating brain disorders such as Parkinson's disease is to drive neuroplasticity in a direction to improve motor and cognitive dysfunction. The purpose of this short review is to present the evidence from our laboratories that supports neuroplasticity as a potential therapeutic target in treating brain disorders. We consider that the enhancement of motor recovery in both animal models of dopamine depletion and in patients with Parkinson's disease is optimized when cognitive circuits are engaged; in other words, the brain is engaged in a learning modality. Therefore, we propose that to be effective in treating Parkinson's disease, physical therapy must employ both skill-based exercise (to drive specific circuits) and aerobic exercise (to drive the expression of molecules required to strengthen synaptic connections) components to select those neuronal circuits, such as the corticostriatal pathway, necessary to restore proper motor and cognitive behaviors. In the wide spectrum of different forms of exercise, learning as the fundamental modality likely links interventions used to treat patients with Parkinson's disease and may be necessary to drive beneficial neuroplasticity resulting in symptomatic improvement and possible disease modification.