Cholinergic interneurons in the rat striatum modulate substitution of habits

Behavioural flexibility is crucial for adaptive behaviour, and recent evidence suggests that cholinergic interneurons of the striatum play a distinct role. Previous studies of cholinergic function have focused on strategy switching by the dorsomedial or ventral striatum. We here investigated whether cholinergic interneurons in the dorsolateral striatum play a similar role at the level of switching of habitual responses. Because the dorsolateral striatum is particularly involved in habitual responding, we developed a habit substitution task that involved switching habitual lever‐press responses to one side to another. We first measured the effect of cholinergic activation in the dorsolateral striatum on this task. Chemogenetic activation of cholinergic interneurons caused an increase in the response rate for the substituted response that was significantly greater than the increase normally seen in control animals. The increase was due to burst‐like responses with shorter inter‐press intervals. However, there was no effect on inhibiting the old habit, or on habitual responding that did not require a switch. There was also no effect on lever‐press performance and its reversal before lever‐press responses became habitual. Conversely, neurochemically specific ablation of cholinergic interneurons did not significantly change habitual responding or response substitution. Thus, activation –but not ablation –of cholinergic interneurons in the dorsolateral striatum modulates expression of a new habit when an old habit is replaced by a new one. Together with previous work, this suggests that striatal cholinergic interneurons facilitate behavioural flexibility in both dorsolateral striatum in addition to dorsomedial and ventral striatum

The Impact of Stress in Decision Making in the Context of Uncertainty

For a number of decades, different fields of knowledge, including psychology, economics, and neurosciences, have focused their research efforts on a better understanding of the decision-making process. Making decisions based on the probability of future events is routine in everyday life; it occurs whenever individuals select an option from several alternatives, each one associated with a specific value. Sometimes subjects decide knowing the precise outcomes of each option, but commonly they have to decide without knowing the consequences (because either ambiguity or risk is involved). Stress has a broad impact on animal behaviors, affects brain regions involved in decision-making processes, and, when maladaptive, is a trigger for neuropsychiatric disorders. This Mini-Review provides a comprehensive overview on how stress impacts decision-making processes, particularly under uncertain conditions. Understanding this can prove to be useful for intervention related to impairments to decision-making processes that present in several stress-triggered neuropsychiatric disorders.Foundation for Science and Technology . Grant Numbers: SFRH/SINTD/60129/2009 , PTDC/SAU-NSC/111814/2009; Programa Operacional Factores de Competitividade (COMPETE)].info:eu-repo/semantics/publishedVersio

Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles

"This is the peer reviewed version of the following article: Llopis-Lorente, Antoni, Paula Díez, Cristina de la Torre, Alfredo Sánchez, Félix Sancenón, Elena Aznar, María D. Marcos, Paloma Martínez-Ruíz, Ramón Martínez-Máñez, and Reynaldo Villalonga. 2017. Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles. Chemistry - A European Journal 23 (18). Wiley: 4276 81. doi:10.1002/chem.201700603, which has been published in final form at https://doi.org/10.1002/chem.201700603. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving."[EN] This work reports a new gated nanodevice for acetylcholine-triggered cargo delivery. We prepared and characterized Janus Au-mesoporous silica nanoparticles functionalized with acetylcholinesterase on the Au face and with supramolecular b-cyclodextrin: benzimidazole inclusion complexes as caps on the mesoporous silica face. The nanodevice is able to selectively deliver the cargo in the presence of acetylcholine via enzyme-mediated acetylcholine hydrolysis, locally lowering the pH and opening the supramolecular gate. Given the key role played by ACh and its relation with Parkinson's disease and other nervous system diseases, we believe that these findings could help design new therapeutic strategies.A.L.L. is grateful to "La Caixa" Banking Foundation for his PhD fellowship. The authors are gratitude to the Spanish Government (MINECO Projects MAT2012-38429-C04-01, MAT2015-64139-C4-1, CTQ2014-58989-P and CTQ2015-71936-REDT) and the Generalitat Valencia (Project PROMETEOII/2014/047) for support. The Comunidad de Madrid (S2013/MIT-3029, Programme NANOAVANSENS) is also gratefully acknowledged.Llopis-Lorente, A.; Díez, P.; De La Torre-Paredes, C.; Sanchez, A.; Sancenón Galarza, F.; Aznar, E.; Marcos Martínez, MD.... (2017). Enzyme-Controlled Nanodevice for Acetylcholine-Triggered Cargo Delivery Based on Janus Au-Mesoporous Silica Nanoparticles. Chemistry - A European Journal. 23(18):4276-4281. https://doi.org/10.1002/chem.201700603S427642812318Gotti, C., & Clementi, F. (2004). Neuronal nicotinic receptors: from structure to pathology. Progress in Neurobiology, 74(6), 363-396. doi:10.1016/j.pneurobio.2004.09.006Lindstrom, J. (1997). Nicotinic acetylcholine receptors in health and disease. Molecular Neurobiology, 15(2), 193-222. doi:10.1007/bf02740634Descarries, L., Gisiger, V., & Steriade, M. (1997). Diffuse transmission by acetylcholine in the CNS. Progress in Neurobiology, 53(5), 603-625. doi:10.1016/s0301-0082(97)00050-6Leblond, L., Beaufort, C., Delerue, F., & Durkin, T. P. (2002). Differential roles for nicotinic and muscarinic cholinergic receptors in sustained visuo-spatial attention? A study using a 5-arm maze protocol in mice. 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Cholinergic Interneurons Are Differentially Distributed in the Human Striatum

BACKGROUND: The striatum (caudate nucleus, CN, and putamen, Put) is a group of subcortical nuclei involved in planning and executing voluntary movements as well as in cognitive processes. Its neuronal composition includes projection neurons, which connect the striatum with other structures, and interneurons, whose main roles are maintaining the striatal organization and the regulation of the projection neurons. The unique electrophysiological and functional properties of the cholinergic interneurons give them a crucial modulating function on the overall striatal response. METHODOLOGY/PRINCIPLE FINDINGS: This study was carried out using stereological methods to examine the volume and density (cells/mm(3)) of these interneurons, as visualized by choline acetyltransferase (ChAT) immunoreactivity, in the following territories of the CN and Put of nine normal human brains: 1) precommissural head; 2) postcommissural head; 3) body; 4) gyrus and 5) tail of the CN; 6) precommissural and 7) postcommissural Put. The distribution of ChAT interneurons was analyzed with respect to the topographical, functional and chemical territories of the dorsal striatum. The CN was more densely populated by cholinergic neurons than the Put, and their density increased along the anteroposterior axis of the striatum with the CN body having the highest neuronal density. The associative territory of the dorsal striatum was by far the most densely populated. The striosomes of the CN precommissural head and the postcommissural Put contained the greatest number of ChAT-ir interneurons. The intrastriosomal ChAT-ir neurons were abundant on the periphery of the striosomes throughout the striatum. CONCLUSIONS/SIGNIFICANCE: All these data reveal that cholinergic interneurons are differentially distributed in the distinct topographical and functional territories of the human dorsal striatum, as well as in its chemical compartments. This heterogeneity may indicate that the posterior aspects of the CN require a special integration of information by interneurons. Interestingly, these striatal regions have been very much left out in functional studies

Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice

We herein provide a thorough description of new transgenic mouse models for dentatorubral–pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and γ-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions

Applied neurophysiology of the horse; implications for training, husbandry and welfare

Understanding the neural circuits underlying equine behaviour has the potential to help optimise strategies of husbandry and training. This review discusses two areas of neurophysiological research in a range of species and relates this information to the horse. The first discussion focuses on mechanisms of learning and motivation and assesses how this information can be applied to improve the training of the horse. The second concerns the identification of the equine neurophysiological phenotype, through behavioural and genetic probes, as a way of improving strategies for optimal equine husbandry and training success. The review finishes by identifying directions for future research with an emphasis on how neurophysiological systems (and thus behaviour) can be modified through strategic husbandry. This review highlights how a neurophysioloigical understanding of horse behaviour can play an important role in attaining the primary objectives of equitation science as well as improving the welfare of the hors

Nanotools for Neuroscience and Brain Activity Mapping

Neuroscience is at a crossroads. Great effort is being invested into deciphering specific neural interactions and circuits. At the same time, there exist few general theories or principles that explain brain function. We attribute this disparity, in part, to limitations in current methodologies. Traditional neurophysiological approaches record the activities of one neuron or a few neurons at a time. Neurochemical approaches focus on single neurotransmitters. Yet, there is an increasing realization that neural circuits operate at emergent levels, where the interactions between hundreds or thousands of neurons, utilizing multiple chemical transmitters, generate functional states. Brains function at the nanoscale, so tools to study brains must ultimately operate at this scale, as well. Nanoscience and nanotechnology are poised to provide a rich toolkit of novel methods to explore brain function by enabling simultaneous measurement and manipulation of activity of thousands or even millions of neurons. We and others refer to this goal as the Brain Activity Mapping Project. In this Nano Focus, we discuss how recent developments in nanoscale analysis tools and in the design and synthesis of nanomaterials have generated optical, electrical, and chemical methods that can readily be adapted for use in neuroscience. These approaches represent exciting areas of technical development and research. Moreover, unique opportunities exist for nanoscientists, nanotechnologists, and other physical scientists and engineers to contribute to tackling the challenging problems involved in understanding the fundamentals of brain function

Pauses in cholinergic interneuron firing exert an inhibitory control on striatal output in vivo

The cholinergic interneurons (CINs) of the striatum are crucial for normal motor and behavioral functions of the basal ganglia. Striatal CINs exhibit tonic firing punctuated by distinct pauses. Pauses occur in response to motivationally significant events, but their function is unknown. Here we investigated the effects of pauses in CIN firing on spiny projection neurons (SPNs) – the output neurons of the striatum – using in vivo whole cell and juxtacellular recordings in mice. We found that optogenetically-induced pauses in CIN firing inhibited subthreshold membrane potential activity and decreased firing of SPNs. During pauses, SPN membrane potential fluctuations became more hyperpolarized and UP state durations became shorter. In addition, short-term plasticity of corticostriatal inputs was decreased during pauses. Our results indicate that, in vivo, the net effect of the pause in CIN firing on SPNs activity is inhibition and provide a novel mechanism for cholinergic control of striatal output