Locomotion and cue-dependent behaviors are modified through corticostriatal signaling whereby short-term increases in dopamine availability can provoke persistent changes in glutamate release that contribute to neuropsychiatric disorders, including Parkinson's disease and drug dependence. We found that withdrawal of mice from repeated amphetamine treatment caused a chronic presynaptic depression (CPD) in glutamate release that was most pronounced in corticostriatal terminals with a low probability of release and lasted Ͼ50 d in treated mice. An amphetamine challenge reversed CPD via a dopamine D1-receptor-dependent paradoxical presynaptic potentiation (PPP) that increased corticostriatal activity in direct pathway medium spiny neurons. This PPP was correlated with locomotor responses after a drug challenge, suggesting that it may underlie the sensitization process. Experiments in brain slices and in vivo indicated that dopamine regulation of acetylcholine release from tonically active interneurons contributes to CPD, PPP, locomotor sensitization, and cognitive ability. Therefore, a chronic decrease in corticostriatal activity during withdrawal is regulated around a new physiological range by tonically active interneurons and returns to normal upon reexposure to amphetamine, suggesting that this paradoxical return of striatal activity to a more stable, normalized state may represent an additional source of drug motivation during abstinence. IntroductionThe neocortex refines volitional movements and goal-directed behaviors through the corticostriatal-basal ganglia-thalamocortical feedback loop (Albin et al., 1989;Jog et al., 1999). The input of this neural network consists of glutamatergic cortical afferents that excite D1-class (D1R) and D2-class dopamine receptor (D2R)-expressing striatal medium-sized spiny neurons (MSNs), which form distinct direct and indirect pathways that promote and suppress competing motor movements, respectively (Pennartz et al., 1994; Nicola et al., 2000). Modulation of these excitatory corticostriatal synapses is determined by the availability of dopamine and acetylcholine, which are necessary for the establishment of reward, attention, and motor learning (Kalivas and Volkow, 2005;Cepeda et al., 2010). Emerging evidence suggests that abnormalities in the availability of these neuromodulators may promote an imbalance between direct and indirect striatal pathways (Beutler et al., 2011;Kozorovitskiy et al., 2012; to produce the motor and neuropsychological symptoms of Parkinsonism and drug dependence Bamford and Cepeda, 2009).Addiction is considered a chronic, allostatic condition (Ahmed and Koob, 2005) characterized by drug seeking behaviors and relapse after withdrawal (Kalivas and Volkow, 2005). Psychostimulants have a high potential for abuse because they acutely increase brain dopamine levels (Sulzer, 2011) and their repeated use can trigger long-lasting changes in striatal glutamate (Pierce et al., 1996; Cornish et al., 1999; and acetylcholine (Abercrombie and DeBoer, 1997;Bamford...

During Pavlovian conditioning, pairing of a neutral conditioned stimulus (CS) with a reward leads to conditioned reward-approach responses (CRs) that are elicited by presentation of the CS. CR behaviors can be sign tracking, in which animals engage the CS, or goal tracking, in which animals go to the reward location. We investigated CR behaviors in mice with only ∼5% of normal dopamine in the striatum using a Pavlovian conditioning paradigm. These mice had severely impaired acquisition of the CR, which was ameliorated by pharmacological restoration of dopamine synthesis with L-dopa. Surprisingly, after they had learned the CR, its expression decayed only gradually in following sessions that were conducted without L-dopa treatment. To assess specific contributions of dopamine signaling in the dorsal or ventral striatum, we performed virus-mediated restoration of dopamine synthesis in completely dopamine-deficient (DD) mice. Mice with dopamine signaling only in the dorsal striatum did not acquire a CR, whereas mice with dopamine signaling only in in the ventral striatum acquired a CR. The CR in mice with dopamine signaling only in the dorsal striatum was restored by subjecting the mice to instrumental training in which they had to interact with the CS to obtain rewards. We conclude that dopamine is essential for learning and performance of CR behavior that is predominantly goal tracking. Furthermore, although dopamine signaling in the ventral striatum is sufficient to support a CR, dopamine signaling only in the dorsal striatum can also support a CR under certain circumstances.

Objective We aimed to determine if the severity of inhalation injury evokes an immune response measurable at the systemic level and to further characterize the balance of systemic pro- and anti-inflammation early after burn and inhalation injury. Summary Background Data Previously we reported that the pulmonary inflammatory response is enhanced with worse grades of inhalation injury, and that those who die from their injuries have a blunted pulmonary immune profile compared to survivors. Methods From August 2007 to June 2011, bronchoscopy was performed on 80 patients admitted to the burn intensive care unit when smoke inhalation was suspected. Of these, inhalation injury was graded into one of five categories (0, 1, 2, 3, and 4), with Grade 0 being the absence of visible injury and Grade 4 corresponding to massive injury. Plasma was collected at the time of bronchoscopy and analyzed for 28 immunomodulating proteins via multiplex bead array or ELISA. Results The concentrations of several plasma immune mediators were increased with worse inhalation injury severity, even after adjusting for age and % TBSA. These included interleukin (IL)-1RA (p=0.002), IL-6 (p=0.002), IL-8 (p=0.026), granulocyte colony stimulating factor (p=0.002), and monocyte chemotactic protein (MCP)-1 (p=0.007). Differences in plasma immune mediator concentrations in surviving and deceased patients were also identified. Briefly, plasma concentrations of IL-1RA, IL-6, IL-8, IL-15, Eotaxin, and MCP-1 were higher in deceased patients compared to survivors (p<0.05 for all), while IL-4 and IL-7 were lower (p<0.05). After adjusting for the effects of age, % TBSA, and inhalation injury grade, plasma IL-1RA remained significantly associated with mortality (OR 3.12, 95% CI 1.03–9.44). Plasma IL-1RA also correlated with % TBSA, inhalation injury grade, fluid resuscitation, Baux score, revised Baux score, Denver score, and the Sequential Organ Failure Assessment score. Conclusion The severity of smoke inhalation injury has systemically reaching effects, which argues in favor of treating inhalation injury in a graded manner. Additionally, several plasma immune mediators measured early after injury were associated with mortality. Of these, IL-1RA appeared to have the strongest correlation with injury severity and outcomes measures, which may explain the blunted pulmonary immune response we previously found in non-survivors.

Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons and produces a movement disorder and cognitive impairment that becomes more extensive with the duration of the disease. To what extent cognitive impairment in advanced PD can be attributed to severe loss of dopamine (DA) signaling is not well understood. Furthermore, it is unclear if the loss of DA neurons contributes to the cognitive impairment caused by the reduction in DA signaling. We generated genetic mouse models with equally severe chronic loss of DA achieved by either extensive ablation of DA neurons or inactivation of DA synthesis from preserved neurons and compared their motor and cognitive performance. Motor behaviors were equally blunted in both models, but we observed that DA neuron ablation caused more severe cognitive deficits than DA depletion. Both models had marked deficits in cue-discrimination learning. Yet, deficits in cue-discrimination learning were more severe in mice with DA neuron ablation and only mice with DA neuron ablation had drastically impaired performance in spatial learning, spatial memory and object memory tests. These results indicate that while a severe reduction in DA signaling results in motor and cognitive impairments, the loss of DA neurons promotes more extensive cognitive deficits and suggest that a loss of additional factors that depend on DA neurons may participate in the progressive cognitive decline found in patients with PD.

Background Delays in receiving follow-up colonoscopy after an abnormal fecal immunochemical test (FIT) result are associated with increased colorectal cancer incidence and mortality. Little is known about patterns of follow-up colonoscopy completion in federally qualified health centers. Methods We abstracted the medical records of health center patients, aged 50–75 years, who had an abnormal FIT result between August 5, 2017 and August 4, 2018 (N = 711). We assessed one-year rates of colonoscopy referral, pre-procedure visit completion, colonoscopy completion, and time to colonoscopy; associations between these outcomes and patient characteristics; and reasons for non-completion found in the medical record. Results Of the 711 patients with an abnormal FIT result, 90% were referred to colonoscopy, but only 52% completed a pre-procedure visit, and 43% completed a colonoscopy within 1 year. Median time to colonoscopy was 83 days (interquartile range: 52–131 days). Pre-procedure visit and colonoscopy completion rates were relatively low in patients aged 65–75 (vs. 50–64), who were uninsured (vs. insured) or had no clinic visit in the prior year (vs. ≥ 1 clinic visit). Common reasons listed for non-completion were that the patient declined, or the provider could not reach the patient. Discussion Efforts to improve follow-up colonoscopy rates in health centers might focus on supporting the care transition from primary to specialty gastroenterology care and emphasize care for older uninsured patients and those having no recent clinic visits. Our findings can inform efforts to improve follow-up colonoscopy uptake, reduce time to colonoscopy receipt, and save lives from colorectal cancer. Trial registration: National Clinical Trial (NCT) Identifier: NCT03925883.

An orphan member of the solute carrier family SLC10, SLC10A4 has been found to be enriched in midbrain and brainstem neurons and has been found to co-localize with and to affect dopamine homeostasis. We generated an SLC10A4 knockout mouse (Slc10a4Δ/Δ) using Cre targeted recombination, and characterized behavioral measures of motor and cognitive function as well as dopamine and acetylcholine levels in midbrain and brainstem. In agreement with previous studies, Slc10a4 mRNA was preferentially expressed in neurons in the brains of wild-type (Slc10a4+/+) mice and was enriched in dopaminergic and cholinergic regions. Slc10a4Δ/Δ mice had no impairment in motor function or novelty-induced exploratory behaviors but performed significantly worse in measures of spatial memory and cognitive flexibility. Slc10a4Δ/Δ mice also did not differ from Slc10a4+/+ in measures of anxiety. HPLC measures on tissue punches taken from the dorsal and ventral striatum reveal a decrease in dopamine content and a corresponding increase in the metabolite DOPAC, indicating an increase in dopamine turnover. Punches taken from the brainstem revealed a decrease in acetylcholine as compared with Slc10a4+/+ littermates. Together, these data indicate that loss of SLC10A4 protein results in neurotransmitter imbalance and cognitive impairment.

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