Opposing Motor Memories in the Direct and Indirect Pathways of the Basal Ganglia.

Loss of dopamine neurons causes motor deterioration in Parkinson's disease patients. We have previously reported that in addition to acute motor impairment, the impaired motor behavior is encoded into long-term memory in an experience-dependent and task-specific manner, a phenomenon we refer to as aberrant inhibitory motor learning. Although normal motor learning and aberrant inhibitory learning oppose each other and this is manifested in apparent motor performance, in the present study, we found that normal motor memory acquired prior to aberrant inhibitory learning remains preserved in the brain, suggesting the existence of independent storage. To investigate the neuronal circuits underlying these two opposing memories, we took advantage of the RNA-binding protein YTHDF1, an m 6 A RNA methylation reader involved in the regulation of protein synthesis and learning/memory. Conditional deletion of Ythdf1 in either D1 or D2 receptor-expressing neurons revealed that normal motor memory is stored in the D1 (direct) pathway of the basal ganglia, while inhibitory memory is stored in the D2 (indirect) pathway. Furthermore, fiber photometry recordings of GCaMP signals from striatal D1 (dSPN) and D2 (iSPN) receptor-expressing neurons support the preservation of normal memory in the direct pathway after aberrant inhibitory learning, with activities of dSPN predictive of motor performance. Finally, a computational model based on activities of motor cortical neurons, dSPN and iSPN neurons, and their interactions through the basal ganglia loops supports the above observations. These findings have important implications for novel approaches in treating Parkinson's disease by reactivating preserved normal memory, and in treating hyperkinetic movement disorders such as chorea or tics by erasing aberrant motor memories.

A cholinergic circuit that relieves pain despite opioid tolerance.

Chronic pain is a tremendous burden for afflicted individuals and society. Although opioids effectively relieve pain, significant adverse outcomes limit their utility and efficacy. To investigate alternate pain control mechanisms, we explored cholinergic signaling in the ventrolateral periaqueductal gray (vlPAG), a critical nexus for descending pain modulation. Biosensor assays revealed that pain states decreased acetylcholine release in vlPAG. Activation of cholinergic projections from the pedunculopontine tegmentum to vlPAG relieved pain, even in opioid-tolerant conditions, through ⍺7 nicotinic acetylcholine receptors (nAChRs). Activating ⍺7 nAChRs with agonists or stimulating endogenous acetylcholine inhibited vlPAG neuronal activity through Ca2+ and peroxisome proliferator-activated receptor α (PPAR⍺)-dependent signaling. In vivo 2-photon imaging revealed that chronic pain induces aberrant excitability of vlPAG neuronal ensembles and that ⍺7 nAChR-mediated inhibition of these cells relieves pain, even after opioid tolerance. Finally, pain relief through these cholinergic mechanisms was not associated with tolerance, reward, or withdrawal symptoms, highlighting its potential clinical relevance.

Pulmonary Hypertension, an Echo Assessment: Is it Arterial or Venous?

Introduction: Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling, right heart failure, and reduced survival. PH can be PH without left ventricular (LV) dysfunction - pulmonary arterial hypertension (PAH) - (Dana point Class I) and PH with LV dysfunction - pulmonary venous hypertension (PVH) - (Dana point Class II). Whatever the underlying cardiac disease, the presence of PH in patients with heart failure is associated with poor prognosis. Right ventricular dysfunction by ventricular interdependence can cause LV dysfunction. Objective: We aim to provide a distinction between PAH and PVH by echocardiography. Methods: Retrospective cross-sectional single-center data of 1075 subjects having PH as defined by echocardiography was collected. These were segregated into mild, moderate, and severe categories. The same cohort of PH subjects was also segregated by E/e' derived pulmonary capillary wedge pressure (PCWP) values. Echocardiographic measurements and effort tolerance in Mets were analyzed. Data for 707 normal subjects were taken from an earlier published study on normative echocardiographic measurements of healthy Indians. Results: Our findings show that PAH and PVH can be distinguished using PCWP value >15 mmHg obtained by applying Nagueh's formulaon E/e'. Conclusion: We recommend that PCWP derived from E/e' should be reported with pulmonary artery systolic pressure measurement to distinguish between PAH and PVH.

Global longitudinal strain, ejection fraction, effort tolerance and normal echocardiography measurements in healthy Indians.

INTRODUCTION: Normative comprehensive echocardiographic measurements data for healthy Indians are not available while data for American and European population is available from American Society of echocardiography and European Society of Cardiology/European Association of Cardio-Vascular Imaging and their publications. Available studies of Indian subjects are small and report only limited measurements with focus on left ventricular (LV) volumes. OBJECTIVE: We aim to provide comprehensive normative echocardiographic data for healthy Indians from a large sample size. METHODS: A retrospective cross-sectional single-center study of 707 healthy Indian adults age and sex segregated which presented detailed and comprehensive echocardiographic measurements including two-dimensional, M-mode, tissue Doppler imaging, speckle tracking echocardiography, chamber volumes, LV ejection fraction (LVEF), global longitudinal strain (GLS), segmental longitudinal strain and effort tolerance. RESULTS: Our findings show healthy Indians, as compared to US and European population, to have higher relative wall thickness. LV volumes, LV mass, LVEF and effort tolerance that were within American Society of Echocardiography described ranges for chamber quantification. Higher GLS values were observed in Indian population compared to European and American population. Women had higher LVEF and GLS values as compared to men and both showed a gradual decline with aging. CONCLUSION: We present normal reference values for echocardiographic measurements in healthy Indian population, which could be used for future reference and comparison work.