RESUMEN
Anterior cingulate cortex (ACC) activity is important for operations that require the ability to integrate multiple experiences over time, such as rule learning, cognitive flexibility, working memory, and long-term memory recall. To shed light on this, we analyzed neuronal activity while rats repeated the same behaviors during hour-long sessions to investigate how activity changed over time. We recorded neuronal ensembles as rats performed a decision-free operant task with varying reward likelihoods at three different response ports (n = 5). Neuronal state space analysis revealed that each repetition of a behavior was distinct, with more recent behaviors more similar than those further apart in time. ACC activity was dominated by a slow, gradual change in low-dimensional representations of neural state space aligning with the pace of behavior. Temporal progression, or drift, was apparent on the top principal component for every session and was driven by the accumulation of experiences and not an internal clock. Notably, these signals were consistent across subjects, allowing us to accurately predict trial numbers based on a model trained on data from a different animal. We observed that non-continuous ramping firing rates over extended durations (tens of minutes) drove the low-dimensional ensemble representations. 40% of ACC neurons' firing ramped over a range of trial lengths and combinations of shorter duration ramping neurons created ensembles that tracked longer durations. These findings provide valuable insights into how the ACC, at an ensemble level, conveys temporal information by reflecting the accumulation of experiences over extended periods.
Asunto(s)
Giro del Cíngulo , Ratas Long-Evans , Giro del Cíngulo/fisiología , Animales , Ratas , Masculino , Neuronas/fisiología , Recompensa , Aprendizaje/fisiología , Condicionamiento Operante/fisiología , Factores de TiempoRESUMEN
Primary sclerosing cholangitis (PSC) and cystic fibrosis (CF) are both slowly progressive cholestatic liver diseases characterized by fibro-obliterative inflammation of the biliary tract. We hypothesized that dysfunction of the CF gene product, cystic fibrosis transmembrane conductance regulator (CFTR), may explain why a subset of patients with inflammatory bowel disease develop PSC. We prospectively evaluated CFTR genotype and phenotype in patients with PSC ( n=19) compared with patients with inflammatory bowel disease and no liver disease ( n=18), primary biliary cirrhosis ( n=17), CF ( n=81), and healthy controls ( n=51). Genetic analysis of the CFTR gene in PSC patients compared with disease controls (primary biliary cirrhosis and inflammatory bowel disease) demonstrated a significantly increased number of mutations/variants in the PSC group (37% vs 8.6% of disease controls, P=0.02). None of the PSC patients carried two mutations/variants. Of PSC patients, 89% carried the 1540G-variant-containing genotypes (resulting in decreased functional CFTR) compared with 57% of disease controls ( P=0.03). Only one of 19 PSC patients had neither a CFTR mutation nor the 1540G variant. CFTR chloride channel function assessed by nasal potential difference testing demonstrated a reduced median isoproterenol response of 14 mV in PSC patients compared with 19 mV in disease controls ( P=0.04) and 21 mV in healthy controls ( P=0.003). These data indicate that there is an increased prevalence of CFTR abnormalities in PSC as demonstrated by molecular and functional analyses and that these abnormalities may contribute to the development of PSC in a subset of patients with inflammatory bowel disease.