Olfaction is a principal sensory modality in rodents, and rats quickly learn to discriminate between odors and to associate odor with reward. Here we show that such olfactory discrimination (OD) learning consists of two phases with distinct cellular mechanisms: an initial NMDAR-sensitive phase in which the animals acquire a successful behavioral strategy (rule learning), followed by an NMDAR-insensitive phase in which the animals learn to distinguish between individual odors (pair learning). Rule learning regulates the composition of synaptic NMDARs in the piriform cortex, resulting in receptors with a higher complement of the NR2a subunit protein relative to NR2b. Rule learning also reduces long-term potentiation (LTP) induced by high-frequency stimulation of the intracortical axons in slices of piriform cortex. As NR2a-containing NMDARs mediate shorter excitatory postsynaptic currents than those containing NR2b, we suggest that learning-induced regulation of NMDAR composition constrains subsequent synaptic plasticity, thereby maintaining the memory encoded by experience.

Learning-related modifications in predisposition for long-term potentiation (LTP) and long-term depression (LTD) were studied in brain slices of the rat piriform cortex following olfactory learning. Rats were trained to discriminate between pairs of odors until they demonstrated rule learning. We have previously shown that such training is accompanied by enhanced neuronal excitability and increased synaptic transmission in the intrinsic synaptic pathway. Here we show that the susceptibility for further enhancing synaptic connectivity by inducing LTP in slices from trained rats is markedly reduced after training, compared with slices from pseudo-trained and naive rats. Accordingly, while 900 stimuli at 1 Hz did not induce LTD in slices from control rats, it induced significant LTD in slices from trained rats. Post-tetanic potentiation (PTP) was also reduced after training, indicating that synaptic release is enhanced after odor learning, as previously suggested. We suggest that learning-related cellular modifications and activity-dependent synaptic plasticity share a common mechanism in the primary olfactory cortex. Our data also support the prediction generated according to the sliding modification threshold theory that learning should be accompanied by reduced capability of inducing LTP and increased susceptibility for LTD induction.

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BackgroundThe presenting symptoms and co-morbidities contributing to mortality in young patients (age < 50 years old) with colorectal cancer (CRC) are poorly understood. We reviewed these features in our patient population with non-hereditary early-onset CRC (EO-CRC). Study aimThis study aimed to assess characteristics of patients with a diagnosis of non-hereditary EO-CRC, including presenting symptoms and metabolic disorders contributing to mortality in underserved areas of southwest Virginia. MethodsIn this retrospective observational study, we selected patients aged 18-50 years with a diagnosis of nonhereditary EO-CRC from 2008 to 2016 at Carilion Roanoke Memorial Hospital. The electronic medical record was queried to identify demographic data, medical history, histopathology results, lab values, and mortality. The cumulative risks of symptoms and co-morbid metabolic disorders was estimated using Kaplan-Meier curves. ResultsWe identified 139 patients with non-hereditary EO-CRC (mean age 41.6 ± 6.9 years). Almost half of these patients were obese (BMI > 30), 30.9% had a diagnosis of hypertension, 29% had hyperlipidemia (HLD), and 17.35% had diabetes mellitus type 2 (DM2). Diagnosis was delayed by 4.5 months from initial presentation, and 17% had advanced disease (stage III/IV). Also, 68.5% of patients were symptomatic with one to three symptoms, most commonly with rectal bleeding (45.3%). The chronicity of HLD (≥5 years) was associated with reduced survival in our patients with EO-CRC. The survival of females with multiple metabolic disorders was reduced compared to females with a single metabolic disorder. ConclusionsMultiple symptoms, chronic HLD, and female gender with multiple metabolic disorders were factors associated with poor outcomes in non-hereditary EO-CRC patients.