Dopamine across timescales and cell types: Relevance for phenotypes in Parkinson's disease progression.

Dopamine neurons in the substantia nigra pars compacta (SNc) synthesize and release dopamine, a critical neurotransmitter for movement and learning. SNc dopamine neurons degenerate in Parkinson's Disease (PD), causing a host of motor and non-motor symptoms. Here, we review recent conceptual advances in our basic understanding of the dopamine system - including our rapidly advancing knowledge of dopamine neuron heterogeneity - with special attention to their importance for understanding PD. In PD patients, dopamine neuron degeneration progresses from lateral SNc to medial SNc, suggesting clinically relevant heterogeneity in dopamine neurons. With technical advances in dopamine system interrogation, we can understand the relevance of this heterogeneity for PD progression and harness it to develop new treatments.

Drug reinforcement impairs cognitive flexibility by inhibiting striatal cholinergic neurons.

Addictive substance use impairs cognitive flexibility, with unclear underlying mechanisms. The reinforcement of substance use is mediated by the striatal direct-pathway medium spiny neurons (dMSNs) that project to the substantia nigra pars reticulata (SNr). Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs), which receive extensive striatal inhibition. Here, we hypothesized that increased dMSN activity induced by substance use inhibits CINs, reducing cognitive flexibility. We found that cocaine administration in rodents caused long-lasting potentiation of local inhibitory dMSN-to-CIN transmission and decreased CIN firing in the dorsomedial striatum (DMS), a brain region critical for cognitive flexibility. Moreover, chemogenetic and time-locked optogenetic inhibition of DMS CINs suppressed flexibility of goal-directed behavior in instrumental reversal learning tasks. Notably, rabies-mediated tracing and physiological studies showed that SNr-projecting dMSNs, which mediate reinforcement, sent axonal collaterals to inhibit DMS CINs, which mediate flexibility. Our findings demonstrate that the local inhibitory dMSN-to-CIN circuit mediates the reinforcement-induced deficits in cognitive flexibility.

Striatal µ-opioid receptor activation triggers direct-pathway GABAergic plasticity and induces negative affect.

Withdrawal from chronic opioid use often causes hypodopaminergic states and negative affect, which may drive relapse. Direct-pathway medium spiny neurons (dMSNs) in the striatal patch compartment contain µ-opioid receptors (MORs). It remains unclear how chronic opioid exposure and withdrawal impact these MOR-expressing dMSNs and their outputs. Here, we report that MOR activation acutely suppressed GABAergic striatopallidal transmission in habenula-projecting globus pallidus neurons. Notably, withdrawal from repeated morphine or fentanyl administration potentiated this GABAergic transmission. Furthermore, intravenous fentanyl self-administration enhanced GABAergic striatonigral transmission and reduced midbrain dopaminergic activity. Fentanyl-activated striatal neurons mediated contextual memory retrieval required for conditioned place preference tests. Importantly, chemogenetic inhibition of striatal MOR+ neurons rescued fentanyl withdrawal-induced physical symptoms and anxiety-like behaviors. These data suggest that chronic opioid use triggers GABAergic striatopallidal and striatonigral plasticity to induce a hypodopaminergic state, which may promote negative emotions and relapse.

Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility.

Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.

Mechanisms and Functional Consequences of Presynaptic Homeostatic Plasticity at Auditory Nerve Synapses.

Multiple forms of homeostasis influence synaptic function under diverse activity conditions. Both presynaptic and postsynaptic forms of homeostasis are important, but their relative impact on fidelity is unknown. To address this issue, we studied auditory nerve synapses onto bushy cells in the cochlear nucleus of mice of both sexes. These synapses undergo bidirectional presynaptic and postsynaptic homeostatic changes with increased and decreased acoustic stimulation. We found that both young and mature synapses exhibit similar activity-dependent changes in short-term depression. Experiments using chelators and imaging both indicated that presynaptic Ca2+ influx decreased after noise exposure, and increased after ligating the ear canal. By contrast, Ca2+ cooperativity was unaffected. Experiments using specific antagonists suggest that occlusion leads to changes in the Ca2+ channel subtypes driving neurotransmitter release. Furthermore, dynamic-clamp experiments revealed that spike fidelity primarily depended on changes in presynaptic depression, with some contribution from changes in postsynaptic intrinsic properties. These experiments indicate that presynaptic Ca2+ influx is homeostatically regulated in vivo to enhance synaptic fidelity.SIGNIFICANCE STATEMENT Homeostatic mechanisms in synapses maintain stable function in the face of different levels of activity. Both juvenile and mature auditory nerve synapses onto bushy cells modify short-term depression in different acoustic environments, which raises the question of what the underlying presynaptic mechanisms are and the relative importance of presynaptic and postsynaptic contributions to the faithful transfer of information. Changes in short-term depression under different acoustic conditions were a result of changes in presynaptic Ca2+ influx. Spike fidelity was affected by both presynaptic and postsynaptic changes after ear occlusion and was only affected by presynaptic changes after noise-rearing. These findings are important for understanding regulation of auditory synapses under normal conditions and also in disorders following noise exposure or conductive hearing loss.

Optogenetic control of alcohol-seeking behavior via the dorsomedial striatal circuit.

Alcohol consumption alters glutamatergic transmission in many brain regions, including the dorsomedial striatum (DMS); this aberrant plasticity is thought to be responsible for alcohol-seeking behavior. Recent studies reported that alcohol induced such plasticity specifically in direct pathway spiny projection neurons (dSPNs) of the DMS. However, it is unknown how this specific change contributes to alcohol-seeking behavior and relapse. Here, we first demonstrated that operant alcohol self-administration increased NMDA receptor activity in DMS dSPNs. Next, we found that optogenetic inhibition of dSPNs reversibly decreased operant lever presses for alcohol and alcohol intake. Furthermore, optogenetic stimulation of corticostriatal inputs at low and moderate frequencies induced reliable LTD in DMS slices. Surprisingly, in vivo delivery of the LTD-inducing protocol increased operant alcohol self-administration; this effect was blocked by a D2R antagonist. Importantly, LTD induction in the presence of both D1 and D2 receptor antagonists produced a long-lasting decrease in operant alcohol self-administration. Our results suggest that suppressing DMS dSPNs activity and their cortical inputs represents a novel treatment mechanism for alcohol use disorder.

A hybrid land-water-environment model for identification of ecological effect and risk under uncertain meteorological precipitation in an agroforestry ecosystem.

In this study, a hybrid land-water-environment (LWE) model is developed for identifying ecological effect and risk under uncertain precipitation in an agroforestry ecosystem. A simulation-based fuzzy-stochastic programming with risk analysis (SFSR) method is used into LWE model to reflect the meteorological impacts; meanwhile, it also can quantify artificial fuzziness (e.g., risk attitude of policymaker) and natural vagueness (e.g., ecological function) in decision-making. The developed LWE model with SFSR method is applied to a practical agroforestry ecosystem in China. Results of optimized planting scale, irrigative water schedule, pollution mitigation scheme, and system benefit under changed rainfall, precise risk-adoption and vague ecological function are obtained; meanwhile their corresponding ecological effects and risks are analyzed. It found that current LWE plans could generate massive water deficits (e.g., 23.22×106m3 in crop irrigation and 26.32×106m3 in forest protection at highest) due to over-cultivation and excessive pollution discharges (e.g., the highest excessive TP and TN discharges would reach 460.64 and 15.30×103 ton) due to irrational fertilization, which would increase regional ecological risks. In addition, fifteen scenarios associated with withdrawing cultivation and recovering forest based on regional environment heterogeneity (such as soil types) have been discussed to adjust current agriculture-environment policies. It found that, the excessive pollution discharges (TN and TP) could be reduced 12.95% and 18.32% at highest through ecological expansions, which would generate higher system benefits than that without withdrawing farmland and recovering forest. All above can facilitate local policymakers to modulate a comprehensive LWE with more sustainable and robust manners, achieving regional harmony between socio-economy and eco-environment.

Changes in Properties of Auditory Nerve Synapses following Conductive Hearing Loss.

Auditory activity plays an important role in the development of the auditory system. Decreased activity can result from conductive hearing loss (CHL) associated with otitis media, which may lead to long-term perceptual deficits. The effects of CHL have been mainly studied at later stages of the auditory pathway, but early stages remain less examined. However, changes in early stages could be important because they would affect how information about sounds is conveyed to higher-order areas for further processing and localization. We examined the effects of CHL at auditory nerve synapses onto bushy cells in the mouse anteroventral cochlear nucleus following occlusion of the ear canal. These synapses, called endbulbs of Held, normally show strong depression in voltage-clamp recordings in brain slices. After 1 week of CHL, endbulbs showed even greater depression, reflecting higher release probability. We observed no differences in quantal size between control and occluded mice. We confirmed these observations using mean-variance analysis and the integration method, which also revealed that the number of release sites decreased after occlusion. Consistent with this, synaptic puncta immunopositive for VGLUT1 decreased in area after occlusion. The level of depression and number of release sites both showed recovery after returning to normal conditions. Finally, bushy cells fired fewer action potentials in response to evoked synaptic activity after occlusion, likely because of increased depression and decreased input resistance. These effects appear to reflect a homeostatic, adaptive response of auditory nerve synapses to reduced activity. These effects may have important implications for perceptual changes following CHL. SIGNIFICANCE STATEMENT: Normal hearing is important to everyday life, but abnormal auditory experience during development can lead to processing disorders. For example, otitis media reduces sound to the ear, which can cause long-lasting deficits in language skills and verbal production, but the location of the problem is unknown. Here, we show that occluding the ear causes synapses at the very first stage of the auditory pathway to modify their properties, by decreasing in size and increasing the likelihood of releasing neurotransmitter. This causes synapses to deplete faster, which reduces fidelity at central targets of the auditory nerve, which could affect perception. Temporary hearing loss could cause similar changes at later stages of the auditory pathway, which could contribute to disorders in behavior.

Determining the optimal 5-FU therapeutic dosage in the treatment of colorectal cancer patients.

Fluorouracil (5-FU) has been wildly used as a primary medication in the treatment of solid tumors including colorectal cancer. The treatment efficacy and toxicity of 5-FU varies greatly among individuals, suggesting a need for individualized regimen for cancer patients. The present study analyzed the blood concentration of 5-FU and its therapeutic efficacy and toxicity, evaluated the relationship of AUC (area under the plasma concentration-time curve), and the protein expression of DPD (dihydropyrimidine dehydrogenase) and TS (thymidylate synthetase), and therapeutic efficacy and toxicity. It was found that the AUC of 5-FU was 34.16±14.83mgmg·h/L in this cohort of study. The immunohistochemical analysis revealed 38.96% and 81.82% positive staining for DPD and TS in colorectal cancer tissues, respectively. We demonstrated that the expression of TS is positively correlated with the expression of DPD. There was a positive correlation between AUC and therapeutic efficacy, and gastrointestinal tract and neural toxicity. The expression of neither DPD nor TS had significant correlations with therapeutic efficacy and toxicity. Based on the blood 5-FU concentration and its relationship with treatment efficacy and toxicity, we determined an optimal therapeutic dosage of 5-FU to be equivalent to an AUC=28.03-38.94mgmg·h/L. Our study will be helpful in providing an individualized medical regimen for the treatment of colorectal cancer patients.

Cancer-related fatigue and chemotherapy-associated adverse effects: correlation with TNF-α, IL-1 and 17-hydroxycorticosteroids.

AIM: We sought to determine the relationship between cancer-related fatigue, chemotherapy-associated adverse effects in patients with advanced stages of cancer, and the levels of TNF-α, IL-1 and 17-hydroxycorticosteroids (17-HCS). PATIENTS & METHODS: Two hundred cancer patients were recruited. They were given a Cancer Fatigue Scale survey to assess their general state of health before and after chemotherapy. Their plasma levels of TNF-α and IL-1 and urine levels of 17-HCS were also measured. RESULTS: Increased levels of TNF-α and IL-1 are common in cancer patients. Thirty-five (17.5%) patients suffered from chemotherapy-associated adverse effects, but their plasma levels of TNF-α and IL-1 were not significantly elevated after chemotherapy. However, the urinary levels of 17-HCS levels were significantly elevated in 23 patients after chemotherapy. CONCLUSION: Patients who had elevated urinary levels of 17-HCS before chemotherapy are accompanied by chemotherapy-associated adverse effects. Thus, elevated 17-HCS in urine could be a possible predictor for chemotherapy-associated adverse effects.