D1 and D2 medium spiny neurons in the nucleus accumbens core have distinct and valence-independent roles in learning.

At the core of value-based learning is the nucleus accumbens (NAc). D1- and D2-receptor-containing medium spiny neurons (MSNs) in the NAc core are hypothesized to have opposing valence-based roles in behavior. Using optical imaging and manipulation approaches in mice, we show that neither D1 nor D2 MSNs signal valence. D1 MSN responses were evoked by stimuli regardless of valence or contingency. D2 MSNs were evoked by both cues and outcomes, were dynamically changed with learning, and tracked valence-free prediction error at the population and individual neuron level. Finally, D2 MSN responses to cues were necessary for associative learning. Thus, D1 and D2 MSNs work in tandem, rather than in opposition, by signaling specific properties of stimuli to control learning.

Dopamine signaling in the nucleus accumbens core mediates latent inhibition.

Studies investigating the neural mechanisms by which associations between cues and predicted outcomes control behavior often use associative learning frameworks to understand the neural control of behavior. These frameworks do not always account for the full range of effects that novelty can have on behavior and future associative learning. Here, in mice, we show that dopamine in the nucleus accumbens core is evoked by novel, neutral stimuli, and the trajectory of this response over time tracked habituation to these stimuli. Habituation to novel cues before associative learning reduced future associative learning, a phenomenon known as latent inhibition. Crucially, trial-by-trial dopamine response patterns tracked this phenomenon. Optogenetic manipulation of dopamine responses to the cue during the habituation period bidirectionally influenced future associative learning. Thus, dopamine signaling in the nucleus accumbens core has a causal role in novelty-based learning in a way that cannot be predicted based on purely associative factors.

Consequences of the first and second COVID-19 wave on kidney transplant recipients at a large Indian transplant centre.

BACKGROUND: There is a scarcity of data comparing the consequences of first and second COVID-19 waves on kidney transplant recipients (KTRs) in India. METHODS: We conducted a single-centre retrospective study of 259 KTRs with COVID-19 to compare first wave (March 15-December 31 2020, n = 157) and second wave (April 1-May 31 2021, n = 102). RESULTS: KTRs during second wave were younger (43 vs. 40 years; p-value .04) and also included paediatric patients (0 vs. 5.9%; p-value .003). Symptoms were milder during the second wave (45 vs. 62.7%; p-value .007); COVID-19 positive patients had less frequent cough (32 vs. 13.8%; p-value .001), fever was less frequent (58 vs. 37%; p-value .001), and we observed fewer co-morbidities (11 vs. 20.6%; p-value .04). The percentages of neutrophils (77 vs. 83%; p-value .001) and serum ferritin (439 vs. 688; p-value .0006) were higher during second wave, while lymphocyte counts were reduced (20 vs. 14%; p-value .0001). Hydroxychloroquine (11 vs. 0%; p-value .0001) and tocilizumab (7 vs. 0%; p-value .004) were more frequently prescribed during first wave, while utilization of dexamethasone (6 vs. 27%; p-value .0001) and remdesivir (47 vs. 65%; p-value .03) increased during the second wave. Mucormycosis (1.3 vs. 10%; p-value .01) and ICU admissions (20 vs. 37.2%; p-value .002) were more frequent during second wave. The 28-day mortality rate (9.6 vs. 10%; p-value 1) was not different. CONCLUSIONS: There has been a different clinical spectrum of COVID-19 amongst KTR with similar mortality between the two waves at a large Indian transplant centre.

Clinical Profiles and Outcomes of COVID-19 in Kidney Transplant Recipients: Experience From a High-Volume Public Sector Transplant Center in India.

OBJECTIVES: Data are so far limited on outcomes of kidney transplant recipients with COVID-19 seen at public sector hospitals in developing countries with limited resources. MATERIALS AND METHODS: We retrospectively investigated a cohort of 157 kidney transplant recipients (75% living and 25% deceased donors) seen at a public sector transplant hospital in India from March to December 2020 who had reverse-transcriptase polymerase chain reaction tests that confirmed COVID-19. Demographic data, immunosuppression regimens, clinical profiles, treatments, and outcomes were analyzed. In our center, maintenance immunosuppression was reduced according to disease severity and case-by-case evaluations. There were also 53 patients with asymptomatic or mild COVID-19 symptoms who received home care to optimize the utilization of scarce resources during travel restrictions. RESULTS: In our kidney transplant recipient group, median age was 43 years (133 male; 24 female patients); recipients presented at a median of 4 years after transplant. The most common comorbidities included arterial hypertension (73%) and diabetes (24%); presenting symptoms at the time of COVID-19 positivity included cough (49%), fever (58%), and sputum production (32%). Clinical severity ranged from asymptomatic (4%), mild (45%), moderate (31%), and severe (20%) disease. Statistically significant risk factors for mortality included older age, dyspnea, severe disease, obesity, allograft dysfunction prior to COVID-19, acute kidney injury, higher levels of inflammatory markers (C-reactive protein, interleukin 6, procalcitonin), abnormality in chest radiography, and intensive care/ventilator requirements (P < .05). Overall patient mortality was 9.5% (15/157) in hospitalized patients, 21% (15/71) in patients in the intensive care unit, 100% (15/15) in patients who required ventilation, and 0% among those in home treatment. CONCLUSIONS: The mortality rate in kidney transplant recipients with COVID-19 was higher than in the nonimmunosuppressed general population (1.2%) in India. To our knowledge, this is a largest single-center study of kidney transplant recipients with COVID-19 so far.