The role of cholinergic system in neuronal plasticity: focus on visual cortex and muscarinic receptors.

Institute of Neuroscience (C.N.R.), 56100 Pisa, Italy.
Archives italiennes de biologie (Impact Factor: 1.42). 10/2008; 146(3-4):165-88.
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    ABSTRACT: Previously we demonstrated that mildronate [3-(2,2,2-trimethylhydrazinium) propionate dihydrate], a representative of the aza-butyrobetaine class of compounds, protects mitochondrial metabolism under conditions such as ischemia. Mildronate also acted as a neuroprotective agent in an azidothymidine-induced mouse model of neurotoxicity, as well as in a rat model of Parkinson's disease. These observations suggest that mildronate may stimulate processes involved in cell survival and change expression of proteins involved in neurogenic processes. The present study investigated the influence of mildronate on learning and memory in the passive avoidance response (PAR) test and the active conditioned avoidance response (CAR) test in rats. The CAR test employed also bromodeoxyuridine (BrdU)-treated animals. Hippocampal cell BrdU incorporation was then immunohistochemically assessed in BrdU-treated, CAR-trained rats to identify proliferating cells. In addition, the expression of hippocampal proteins which could serve as memory enhancement biomarkers was evaluated and compared to non-trained animals' data. These biomarkers included glutamic acid decarboxylase 65/67 (GAD65/67), acetylcholine esterase (AChE), growth-associated protein-43 (GAP-43) and the transcription factor c-jun/activator protein-1 (AP-1). The results showed that mildronate enhanced learning/memory formation that coincided with the proliferation of neural progenitor cells, changing/regulating of the expression of biomarker proteins which are involved in the activation of glutamatergic and cholinergic pathways, transcription factors and adhesion molecule. The data from our study suggest that mildronate may be useful as a possible cognitive enhancer for the treatment of patients with neurodegenerative diseases with dementia.
    Pharmacology Biochemistry and Behavior 03/2013; 106. DOI:10.1016/j.pbb.2013.03.012 · 2.82 Impact Factor
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    ABSTRACT: CONTEXT The need for improved treatment options for patients with major depressive disorder (MDD) is critical. Faster-acting antidepressants and biomarkers that predict clinical response will facilitate treatment. Scopolamine produces rapid antidepressant effects and thus offers the opportunity to characterize potential biomarkers of treatment response within short periods. OBJECTIVE To determine if baseline brain activity when processing emotional information can predict treatment response to scopolamine in MDD. DESIGN A double-blind, placebo-controlled, crossover study together with repeated functional magnetic resonance imaging, acquired as participants performed face-identity and face-emotion working memory tasks. SETTING National Institute of Mental Health Division of Intramural Research Programs. PARTICIPANTS Fifteen currently depressed outpatients meeting DSM-IV criteria for recurrent MDD and 21 healthy participants, between 18 and 55 years of age. MAIN OUTCOME MEASURE The magnitude of treatment response to scopolamine (percentage of change in the Montgomery-Asberg Depression Rating Scale score between study end and baseline) was correlated with blood oxygen level-dependent (BOLD) signal associated with each working memory component (encode, maintenance, and test) for both identity and emotion tasks. Treatment response also was correlated with change in BOLD response (scopolamine vs baseline). Baseline activity was compared between healthy and MDD groups. RESULTS Baseline BOLD response in the bilateral middle occipital cortex, selectively during the stimulus-processing components of the emotion working memory task (no correlation during the identity task), correlated with treatment response magnitude. Change in BOLD response following scopolamine administration in overlapping areas in the middle occipital cortex while performing the same task conditions also correlated with clinical response. Healthy controls showed higher activity in the same visual regions than patients with MDD during baseline. CONCLUSION These results implicate cholinergic and visual processing dysfunction in the pathophysiology of MDD and suggest that neural response in the visual cortex, selectively to emotional stimuli, may provide a useful biomarker for identifying patients who will respond favorably to scopolamine. TRIAL REGISTRATION Identifier:NCT00055575.
    JAMA Psychiatry 01/2013; 70(3):1-11. DOI:10.1001/2013.jamapsychiatry.60 · 12.01 Impact Factor
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    ABSTRACT: Neurons in rodent primary visual cortex (V1) relate operantly conditioned stimulus-reward intervals with modulated patterns of spiking output, but little is known about the locus or mechanism of this plasticity. Here we show that cholinergic basal forebrain projections to V1 are necessary for the neural acquisition, but not the expression, of reward timing in the visual cortex of awake, behaving animals. We then mimic reward timing in vitro by pairing white matter stimulation with muscarinic receptor activation at a fixed interval and show that this protocol results in the prolongation of electrically evoked spike train durations out to the conditioned interval. Together, these data suggest that V1 possesses the circuitry and plasticity to support reward time prediction learning and the cholinergic system serves as an important reinforcement signal which, in vivo, conveys to the cortex the outcome of behavior.
    Neuron 02/2013; 77(4):723-35. DOI:10.1016/j.neuron.2012.12.039 · 15.98 Impact Factor

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