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1.  A Role for MicroRNA-155 Expression in Microenvironment Associated to HPV-Induced Carcinogenesis in K14-HPV16 Transgenic Mice 
PLoS ONE  2015;10(1):e0116868.
Human Papillomavirus cause a number of diseases most notably cervical cancer. K14-HPV16 transgenic mice expressing the HPV16 early genes in squamous epithelial cells provide a suitable experimental model for studying these diseases. MicroRNAs are small non-coding RNAs that play an important role in regulating gene expression and have been suggested to play an important role in cancer development. The role of miR-155 in cancer remains controversial and there is limited evidence linking this miRNA to HPV- associated diseases. We hypothesized that miR-155 expression modulates each tissue’s susceptibility to develop HPV-associated carcinogenesis. In this study, we analyzed miR-155 expression in ear and chest skin samples from 22-26 weeks old, female K14-HPV16 transgenic (HPV16+/-) and wild-type (HPV-/-) mice. Among wild-type mice the expression of miR-155 was lower in ear skin compared with chest skin (p = 0.028). In transgenic animals, in situ carcinoma was present in all ear samples whereas chest tissues only showed epidermal hyperplasia. Furthermore, in hyperplastic chest skin samples, miR-155 expression was lower than in normal chest skin (p = 0,026). These results suggest that miR-155 expression may modulate the microenvironmental susceptibility to cancer development and that high miR155 levels may be protective against the carcinogenesis induced by HPV16.
doi:10.1371/journal.pone.0116868
PMCID: PMC4308071  PMID: 25625305
2.  Premotor cortex is critical for goal-directed actions 
Shifting between motor plans is often necessary for adaptive behavior. When faced with changing consequences of one’s actions, it is often imperative to switch from automatic actions to deliberative and controlled actions. The pre-supplementary motor area (pre-SMA) in primates, akin to the premotor cortex (M2) in mice, has been implicated in motor learning and planning, and action switching. We hypothesized that M2 would be differentially involved in goal-directed actions, which are controlled by their consequences vs. habits, which are more dependent on their past reinforcement history and less on their consequences. To investigate this, we performed M2 lesions in mice and then concurrently trained them to press the same lever for the same food reward using two different schedules of reinforcement that differentially bias towards the use of goal-directed versus habitual action strategies. We then probed whether actions were dependent on their expected consequence through outcome revaluation testing. We uncovered that M2 lesions did not affect the acquisition of lever-pressing. However, in mice with M2 lesions, lever-pressing was insensitive to changes in expected outcome value following goal-directed training. However, habitual actions were intact. We confirmed a role for M2 in goal-directed but not habitual actions in separate groups of mice trained on the individual schedules biasing towards goal-directed versus habitual actions. These data indicate that M2 is critical for actions to be updated based on their consequences, and suggest that habitual action strategies may not require processing by M2 and the updating of motor plans.
doi:10.3389/fncom.2013.00110
PMCID: PMC3740264  PMID: 23964233
premotor cortex; goal-directed actions; habitual actions; value-based decision making; action selection
3.  Dissociable Effects of Dopamine on Neuronal Firing Rate and Synchrony in the Dorsal Striatum 
Previous studies showed that dopamine depletion leads to both changes in firing rate and in neuronal synchrony in the basal ganglia. Since dopamine D1 and D2 receptors are preferentially expressed in striatonigral and striatopallidal medium spiny neurons, respectively, we investigated the relative contribution of lack of D1 and/or D2-type receptor activation to the changes in striatal firing rate and synchrony observed after dopamine depletion. Similar to what was observed after dopamine depletion, co-administration of D1 and D2 antagonists to mice chronically implanted with multielectrode arrays in the striatum caused significant changes in firing rate, power of the local field potential (LFP) oscillations, and synchrony measured by the entrainment of neurons to striatal local field potentials. However, although blockade of either D1 or D2 type receptors produced similarly severe akinesia, the effects on neural activity differed. Blockade of D2 receptors affected the firing rate of medium spiny neurons and the power of the LFP oscillations substantially, but it did not affect synchrony to the same extent. In contrast, D1 blockade affected synchrony dramatically, but had less substantial effects on firing rate and LFP power. Furthermore, there was no consistent relation between neurons changing firing rate and changing LFP entrainment after dopamine blockade. Our results suggest that the changes in rate and entrainment to the LFP observed in medium spiny neurons after dopamine depletion are somewhat dissociable, and that lack of D1- or D2-type receptor activation can exert independent yet interactive pathological effects during the progression of Parkinson's disease.
doi:10.3389/neuro.07.028.2009
PMCID: PMC2784296  PMID: 19949467
oscillations; Parkinson's disease; local field potentials; entrainment; movement; caudate; putamen
4.  Endocannabinoid signaling is critical for habit formation 
Extended training can induce a shift in behavioral control from goal-directed actions, which are governed by action-outcome contingencies and sensitive to change in the expected value of the outcome, to habits which are less dependent on action-outcome relations and insensitive to changes in outcome value. Previous studies in rats have shown that interval schedules of reinforcement favor habit formation while ratio schedules favor goal-directed behavior. However, the molecular mechanisms underlying habit formation are not well understood. Endocannabinoids, which can function as retrograde messengers acting through presynaptic CB1 receptors, are highly expressed in the dorsolateral striatum, a key region involved in habit formation. Using a reversible devaluation paradigm, we confirmed that in mice random interval schedules also favor habit formation compared with random ratio schedules. We also found that training with interval schedules resulted in a preference for exploration of a novel lever, whereas training with ratio schedules resulted in less generalization and more exploitation of the reinforced lever. Furthermore, mice carrying either a heterozygous or a homozygous null mutation of the cannabinoid receptor type I (CB1) showed reduced habit formation and enhanced exploitation. The impaired habit formation in CB1 mutant mice cannot be attributed to chronic developmental or behavioral abnormalities because pharmacological blockade of CB1 receptors specifically during training also impairs habit formation. Taken together our data suggest that endocannabinoid signaling is critical for habit formation.
doi:10.3389/neuro.07.006.2007
PMCID: PMC2526012  PMID: 18958234
habit; reward; decision-making; plasticity; action; dopamine; exploration
5.  Endocannabinoid Signaling is Critical for Habit Formation 
Extended training can induce a shift in behavioral control from goal-directed actions, which are governed by action-outcome contingencies and sensitive to changes in the expected value of the outcome, to habits which are less dependent on action-outcome relations and insensitive to changes in outcome value. Previous studies in rats have shown that interval schedules of reinforcement favor habit formation while ratio schedules favor goal-directed behavior. However, the molecular mechanisms underlying habit formation are not well understood. Endocannabinoids, which can function as retrograde messengers acting through presynaptic CB1 receptors, are highly expressed in the dorsolateral striatum, a key region involved in habit formation. Using a reversible devaluation paradigm, we confirmed that in mice random interval schedules also favor habit formation compared with random ratio schedules. We also found that training with interval schedules resulted in a preference for exploration of a novel lever, whereas training with ratio schedules resulted in less generalization and more exploitation of the reinforced lever. Furthermore, mice carrying either a heterozygous or a homozygous null mutation of the cannabinoid receptor type I (CB1) showed reduced habit formation and enhanced exploitation. The impaired habit formation in CB1 mutant mice cannot be attributed to chronic developmental or behavioral abnormalities because pharmacological blockade of CB1 receptors specifically during training also impairs habit formation. Taken together our data suggest that endocannabinoid signaling is critical for habit formation.
doi:10.3389/neuro.07.006.2007
PMCID: PMC2526012  PMID: 18958234
habit; reward; decision-making; plasticity; action; dopamine; exploration
6.  Basal Ganglia Subcircuits Distinctively Encode the Parsing and Concatenation of Action Sequences 
Nature neuroscience  2014;17(3):423-430.
Chunking allows the brain to efficiently organize memories and actions. Although basal ganglia circuits have been implicated in action chunking, little is known about how individual elements are concatenated into a behavioral sequence at the neural level. Using a task where mice learn rapid action sequences, we uncovered neuronal activity encoding entire sequences as single actions in basal ganglia circuits. Besides start/stop activity signaling sequence parsing, we found neurons displaying inhibited or sustained activity throughout the execution of an entire sequence. This sustained activity covaried with the rate of execution of individual sequence elements, consistent with motor concatenation. Direct and indirect pathways of basal ganglia were concomitantly active during sequence initiation, but behaved differently during sequence performance, revealing a more complex functional organization of these circuits than previously postulated. These results have important implications for understanding the functional organization of basal ganglia during the learning and execution of action sequences.
doi:10.1038/nn.3632
PMCID: PMC3955116  PMID: 24464039
7.  Deep brain optical measurements of cell type–specific neural activity in behaving mice 
Nature protocols  2014;9(6):1213-1228.
Recent advances in genetically encoded fluorescent sensors enable the monitoring of cellular events from genetically defined groups of neurons in vivo. In this protocol, we describe how to use a time-correlated single-photon counting (tcspc)–based fiber optics system to measure the intensity, emission spectra and lifetime of fluorescent biosensors expressed in deep brain structures in freely moving mice. When combined with cre-dependent selective expression of genetically encoded ca2+ indicators (GecIs), this system can be used to measure the average neural activity from a specific population of cells in mice performing complex behavioral tasks. as an example, we used viral expression of GcaMps in striatal projection neurons (spns) and recorded the fluorescence changes associated with calcium spikes from mice performing a lever-pressing operant task. the whole procedure, consisting of virus injection, behavior training and optical recording, takes 3–4 weeks to complete. With minor adaptations, this protocol can also be applied to recording cellular events from other cell types in deep brain regions, such as dopaminergic neurons in the ventral tegmental area. the simultaneously recorded fluorescence signals and behavior events can be used to explore the relationship between the neural activity of specific brain circuits and behavior.
doi:10.1038/nprot.2014.080
PMCID: PMC4100551  PMID: 24784819
8.  Concurrent Activation of Striatal Direct and Indirect Pathways During Action Initiation 
Nature  2013;494(7436):238-242.
Summary
The basal ganglia are subcortical nuclei that control voluntary actions, and are affected by a number of debilitating neurological disorders1–4. The prevailing model of basal ganglia function proposes that two orthogonal projection circuits originating from distinct populations of spiny projection neurons (SPNs) in the striatum5,6 - the so-called direct and indirect pathways - have opposing effects on movement: while activity of direct-pathway SPNs purportedly facilitates movement, activity of indirect-pathway SPNs inhibits movement1,2. This model has been difficult to test due to the lack of methods to selectively measure the activity of direct- and indirect-pathway SPNs in freely moving animals. We developed a novel in-vivo method that allowed us to specifically measure direct- and indirect-pathway SPN activity using Cre-dependent viral expression of the genetically encoded calcium indicator (GECI) GCAMP3 in the dorsal striatum of D1-Cre (direct-pathway specific6,7) and A2A-Cre (indirect-pathway specific8,9) mice10. Using fiber optics and time-correlated single photon counting (TCSPC) in mice performing an operant task, we observed transient increases in neural activity in both direct- and indirect-pathway SPNs when animals initiated actions, but not when they were inactive. Concurrent activation of SPNs from both pathways in one hemisphere preceded the initiation of contraversive movements, and predicted the occurrence of specific movements within 500 ms. These observations challenge the classical view of basal ganglia function, and may have implications for understanding the origin of motor symptoms in basal ganglia disorders.
doi:10.1038/nature11846
PMCID: PMC4039389  PMID: 23354054
9.  Orbitofrontal and striatal circuits dynamically encode the shift between goal-directed and habitual actions 
Nature communications  2013;4:2264.
Shifting between goal-directed and habitual actions allows for efficient and flexible decision-making. Here we demonstrate a novel, within-subject instrumental lever-pressing paradigm where mice shift between goal-directed and habitual actions. We identify a role for orbitofrontal cortex (OFC) in actions following outcome-revaluation, and confirm that dorsal medial (DMS) and lateral striatum (DLS) mediate different action strategies. In-vivo simultaneous recordings of OFC, DMS, and DLS neuronal ensembles during shifting reveal that the same neurons display different activity depending on whether presses are goal-directed or habitual, with DMS and OFC becoming more—and DLS less-engaged during goal-directed actions. Importantly, the magnitude of neural activity changes in OFC following changes in outcome value positively correlates with the level of goal-directed behavior. Chemogenetic inhibition of OFC disruptsgoal-directed actions, while optogenetic activation of OFC specifically increases goal-directed pressing. They also reveal a role for OFC in action revaluation, which has implications for understanding compulsive behavior.
doi:10.1038/ncomms3264
PMCID: PMC4026062  PMID: 23921250
10.  Dopamine systems adaptation during acquisition and consolidation of a skill 
The striatum plays a key role in motor learning. Striatal function depends strongly on dopaminergic neurotransmission, but little is known about neuroadaptions of the dopamine system during striatal learning. Using an established task that allows differentiation between acquisition and consolidation of motor learning, we here investigate D1 and D2-like receptor binding and transcriptional levels after initial and long-term training of mice. We found profound reduction in D1 binding within the dorsomedial striatum (DMS) after the first training session on the accelerated rotarod and a progressive reduction in D2-like binding within the dorsolateral striatum (DLS) after extended training. Given that similar phase- and region-specific striatal neuroadaptations have been found also during learning of complex procedural tasks including habit formation and automatic responding, the here observed neurochemical alterations are important for our understanding of neuropsychiatric disorders that show a dysbalance in the function of striatal circuits, such as in addictive behaviors.
doi:10.3389/fnint.2014.00087
PMCID: PMC4220658  PMID: 25414648
dopamine receptors; receptor binding; rotarod; striatum; gene expression; neuroadaptation; learning
11.  Different dorsal striatum circuits mediate action discrimination and action generalization 
The European Journal of Neuroscience  2012;35(7):1105-1114.
Generalization is an important process that allows animals to extract rules from regularities of past experience and apply them to analogous situations. In particular, the generalization of previously learned actions to novel instruments allows animals to use past experience to act faster and more efficiently in an ever-changing environment. However, generalization of actions to a dissimilar instrument or situation may also be detrimental. In this study, we investigate the neural bases of action generalization and discrimination in mice trained on a lever-pressing task. Using specific schedules of reinforcement known to bias animals towards habitual or goal-directed behaviors, we confirmed that action generalization is more prominent in animals using habitual rather than goal-directed strategies. We uncovered that selective excitotoxic lesions of the dorsolateral and dorsomedial striatum have opposite effects on the generalization of a previously learned action to a novel lever. While lesions of the dorsolateral striatum impair action generalization, dorsomedial striatum lesions affect action discrimination and bias subjects towards action generalization. Importantly, these lesions do not affect the ability of animals to explore or match their lever-pressing rate to the reinforcement rate, or the ability to distinguish between different levers. The data presented here reveal that dorsolateral and dorsomedial striatal circuits have opposing roles in the generalization of previously learned actions to novel instruments, and suggest that these circuits compete for the expression of generalization in novel situations.
doi:10.1111/j.1460-9568.2012.08073.x
PMCID: PMC3325510  PMID: 22487040
habit; goal-directed; basal ganglia; motor; learning; memory
12.  Start/Stop Signals Emerge in Nigrostriatal Circuits during Sequence Learning 
Nature  2010;466(7305):457-462.
Summary
Learning new action sequences subserves a plethora of different abilities like escaping a predator, playing a piano, or producing fluent speech. Proper initiation and termination of each action sequence is critical for the organization of behavior, and is compromised in nigrostriatal disorders like Parkinson's and Huntington's disease. Using a self-paced operant task in which mice learn to perform a particular sequence of actions to obtain an outcome, we uncovered neural activity in nigrostriatal circuits specifically signaling the initiation or the termination of each action sequence. This start/stop activity emerged during sequence learning, was specific for particular actions, and did not reflect interval timing, movement speed or action value. Furthermore, genetically altering the function of striatal circuits disrupted the development of start/stop activity and selectively impaired sequence learning. These results have important implications for understanding the functional organization of actions, and sequence initiation and termination impairments observed in basal ganglia disorders.
doi:10.1038/nature09263
PMCID: PMC3477867  PMID: 20651684
13.  CORTICOSTRIATAL PLASTICITY IS NECESSARY FOR LEARNING INTENTIONAL NEUROPROSTHETIC SKILLS 
Nature  2012;483(7389):331-335.
The ability to learn new skills and perfect them with practice applies not only to physical skills but also to abstract skills1, like motor planning or neuroprosthetic actions. Although plasticity in corticostriatal circuits has been implicated in learning physical skills2–4, it remains unclear if similar circuits or processes are required for abstract skill learning. We utilized a novel behavioral paradigm in rodents to investigate the role of corticostriatal plasticity in abstract skill learning. Rodents learned to control the pitch of an auditory cursor to reach one of two targets by modulating activity in primary motor cortex irrespective of physical movement. Degradation of the relation between action and outcome, as well as sensory-specific devaluation and omission tests, demonstrated that these learned neuroprosthetic actions were intentional and goal-directed, rather than habitual. Striatal neurons changed their activity with learning, with more neurons modulating their activity in relation to target-reaching as learning progressed. Concomitantly, strong relations between the activity of neurons in motor cortex and the striatum emerged. Specific deletion of striatal NMDA receptors impaired the development of this corticostriatal plasticity, and disrupted the ability to learn neuroprosthetic skills. These results suggest that corticostriatal plasticity is necessary for abstract skill learning, and that neuroprosthetic movements capitalize on the neural circuitry involved in natural motor learning.
doi:10.1038/nature10845
PMCID: PMC3477868  PMID: 22388818
14.  Chronic Toxoplasma Infection Modifies the Structure and the Risk of Host Behavior 
PLoS ONE  2012;7(3):e32489.
The intracellular parasite Toxoplasma has an indirect life cycle, in which felids are the definitive host. It has been suggested that this parasite developed mechanisms for enhancing its transmission rate to felids by inducing behavioral modifications in the intermediate rodent host. For example, Toxoplasma-infected rodents display a reduction in the innate fear of predator odor. However, animals with Toxoplasma infection acquired in the wild are more often caught in traps, suggesting that there are manipulations of intermediate host behavior beyond those that increase predation by felids. We investigated the behavioral modifications of Toxoplasma-infected mice in environments with exposed versus non-exposed areas, and found that chronically infected mice with brain cysts display a plethora of behavioral alterations. Using principal component analysis, we discovered that most of the behavioral differences observed in cyst-containing animals reflected changes in the microstructure of exploratory behavior and risk/unconditioned fear. We next examined whether these behavioral changes were related to the presence and distribution of parasitic cysts in the brain of chronically infected mice. We found no strong cyst tropism for any particular brain area but found that the distribution of Toxoplasma cysts in the brain of infected animals was not random, and that particular combinations of cyst localizations changed risk/unconditioned fear in the host. These results suggest that brain cysts in animals chronically infected with Toxoplasma alter the fine structure of exploratory behavior and risk/unconditioned fear, which may result in greater capture probability of infected rodents. These data also raise the possibility that selective pressures acted on Toxoplasma to broaden its transmission between intermediate predator hosts, in addition to felid definitive hosts.
doi:10.1371/journal.pone.0032489
PMCID: PMC3303785  PMID: 22431975
15.  Limited Role of Secreted Aspartyl Proteinases Sap1 to Sap6 in Candida albicans Virulence and Host Immune Response in Murine Hematogenously Disseminated Candidiasis▿  
Infection and Immunity  2010;78(11):4839-4849.
Candida albicans secreted aspartyl proteinases (Saps) are considered virulence-associated factors. Several members of the Sap family were claimed to play a significant role in the progression of candidiasis established by the hematogenous route. This assumption was based on the observed attenuated virulence of sap-null mutant strains. However, the exclusive contribution of SAP genes to their attenuated phenotype was not unequivocally confirmed, as the Ura status of these mutant strains could also have contributed to the attenuation. In this study, we have reassessed the importance of SAP1 to SAP6 in a murine model of hematogenously disseminated candidiasis using sap-null mutant strains not affected in their URA3 gene expression and compared their virulence phenotypes with those of Ura-blaster sap mutants. The median survival time of BALB/c mice intravenously infected with a mutant strain lacking SAP1 to SAP3 was equivalent to that of mice infected with wild-type strain SC5314, while those infected with mutant strains lacking SAP5 showed slightly extended survival times. Nevertheless, no differences could be observed between the wild type and a Δsap456 mutant in their abilities to invade mouse kidneys. Likewise, a deficiency in SAP4 to SAP6 had no noticeable impact on the immune response elicited in the spleens and kidneys of C. albicans-infected mice. These results contrast with the behavior of equivalent Ura-blaster mutants, which presented a significant reduction in virulence. Our results suggest that Sap1 to Sap6 do not play a significant role in C. albicans virulence in a murine model of hematogenously disseminated candidiasis and that, in this model, Sap1 to Sap3 are not necessary for successful C. albicans infection.
doi:10.1128/IAI.00248-10
PMCID: PMC2976357  PMID: 20679440
16.  Impaired Synaptic Plasticity and Motor Learning in Mice with a Point Mutation Implicated in Human Speech Deficits 
Current biology : CB  2008;18(5):354-362.
Summary
The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene [1]. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language [2]. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning [3, 4]. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits.
doi:10.1016/j.cub.2008.01.060
PMCID: PMC2917768  PMID: 18328704
17.  Dynamic reorganization of striatal circuits during the acquisition and consolidation of a skill 
Nature neuroscience  2009;12(3):333-341.
The learning of new skills is characterized by an initial phase of rapid improvement in performance and a phase of more gradual improvements as skills are automatized and performance asymptotes. Using in vivo striatal recordings, we observed region-specific changes in neural activity during the different phases of skill learning, with the associative or dorsomedial striatum being preferentially engaged early in training and the sensorimotor or dorsolateral striatum being engaged later in training. Ex vivo recordings from medium spiny striatal neurons in brain slices of trained mice revealed that the changes observed in vivo corresponded to regional- and training-specific changes in excitatory synaptic transmission in the striatum. Furthermore, the potentiation of glutamatergic transmission observed in dorsolateral striatum after extensive training was preferentially expressed in striatopallidal neurons, rather than striatonigral neurons. These findings demonstrate that region- and pathway-specific plasticity sculpts the circuits involved in the performance of the skill as it becomes automatized.
doi:10.1038/nn.2261
PMCID: PMC2774785  PMID: 19198605
18.  Instrumental Uncertainty as a Determinant of Behavior Under Interval Schedules of Reinforcement 
Interval schedules of reinforcement are known to generate habitual behavior, the performance of which is less sensitive to revaluation of the earned reward and to alterations in the action-outcome contingency. Here we report results from experiments using different types of interval schedules of reinforcement in mice to assess the effect of uncertainty, in the time of reward availability, on habit formation. After limited training, lever pressing under fixed interval (FI, low interval uncertainty) or random interval schedules (RI, higher interval uncertainty) was sensitive to devaluation, but with more extended training, performance of animals trained under RI schedules became more habitual, i.e. no longer sensitive to devaluation, whereas performance of those trained under FI schedules remained goal-directed. When the press-reward contingency was reversed by omitting reward after pressing but presenting reward in the absence of pressing, lever pressing in mice previously trained under FI decreased more rapidly than that of mice trained under RI schedules. Further analysis revealed that action-reward contiguity is significantly reduced in lever pressing under RI schedules, whereas action-reward correlation is similar for the different schedules. Thus the extent of goal-directedness could vary as a function of uncertainty about the time of reward availability. We hypothesize that the reduced action-reward contiguity found in behavior generated under high uncertainty is responsible for habit formation.
doi:10.3389/fnint.2010.00017
PMCID: PMC2901087  PMID: 20725502
interval schedule of reinforcement; basal ganglia; learning; devaluation; reward; uncertainty; degradation; omission
20.  Neurofibromin regulation of ERK signaling modulates GABA release and learning 
Cell  2008;135(3):549-560.
Summary
We uncovered a new role for ERK signaling in GABA release, long-term potentiation (LTP) and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for Neurofibromatosis type I (NF1), a common genetic cause for learning disabilities. Genetic, pharmacological, electrophysiological and behavioral data demonstrate that neurofibromin modulates ERK/synapsin I dependent GABA release, which in turn modulate hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased pre-synaptic GABA release in the hippocampus which was reversed by pharmacologically down-regulating ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a sub-threshold dose of a GABAA antagonist. Accordingly, Cre-deletions of the Nf1 gene showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning and memory.
doi:10.1016/j.cell.2008.09.060
PMCID: PMC2673196  PMID: 18984165
21.  High on Habits 
Frontiers in Neuroscience  2008;2(2):208-217.
The neural circuits involved in learning and executing goal-directed actions, which are governed by action-outcome contingencies and sensitive to changes in the expected value of the outcome, have been shown to be different from those mediating habits, which are less dependent on action-outcome relations and changes in outcome value. Extended training, different reinforcement schedules, and substances of abuse have been shown to induce a shift from goal-directed performance to habitual performance. This shift can be beneficial in everyday life, but can also lead to loss of voluntary control and compulsive behavior, namely during drug seeking in addiction. Although the brain circuits underlying habit formation are becoming clearer, the molecular mechanisms underlying habit formation are still not understood. Here, we review a recent study where Hilario et al. (2007) established behavioral procedures to investigate habit formation in mice in order to investigate the molecular mechanisms underlying habit formation. Using those procedures, and a combination of genetic and pharmacological tools, the authors showed that endocannabinoid signaling is critical for habit formation.
doi:10.3389/neuro.01.030.2008
PMCID: PMC2622741  PMID: 19225594
striatum; endocannabinoids; dopamine; goal-directed; habits
22.  Impaired Synaptic Plasticity and Motor Learning in Mice with a Point Mutation Implicated in Human Speech Deficits 
Current Biology  2008;18(5):354-362.
Summary
The most well-described example of an inherited speech and language disorder is that observed in the multigenerational KE family, caused by a heterozygous missense mutation in the FOXP2 gene [1]. Affected individuals are characterized by deficits in the learning and production of complex orofacial motor sequences underlying fluent speech and display impaired linguistic processing for both spoken and written language [2]. The FOXP2 transcription factor is highly similar in many vertebrate species, with conserved expression in neural circuits related to sensorimotor integration and motor learning [3, 4]. In this study, we generated mice carrying an identical point mutation to that of the KE family, yielding the equivalent arginine-to-histidine substitution in the Foxp2 DNA-binding domain. Homozygous R552H mice show severe reductions in cerebellar growth and postnatal weight gain but are able to produce complex innate ultrasonic vocalizations. Heterozygous R552H mice are overtly normal in brain structure and development. Crucially, although their baseline motor abilities appear to be identical to wild-type littermates, R552H heterozygotes display significant deficits in species-typical motor-skill learning, accompanied by abnormal synaptic plasticity in striatal and cerebellar neural circuits.
doi:10.1016/j.cub.2008.01.060
PMCID: PMC2917768  PMID: 18328704
SYSNEURO
23.  CD117 immunoexpression in canine mast cell tumours: correlations with pathological variables and proliferation markers 
Background
Cutaneous mast cell tumours are one of the most common neoplasms in dogs and show a highly variable biologic behaviour. Several prognosis tools have been proposed for canine mast cell tumours, including histological grading and cell proliferation markers. CD117 is a receptor tyrosine kinase thought to play a key role in human and canine mast cell neoplasms. Normal (membrane-associated) and aberrant (cytoplasmic, focal or diffuse) CD117 immunoexpression patterns have been identified in canine mast cell tumours. Cytoplasmic CD117 expression has been found to correlate with higher histological grade and with a worsened post-surgical prognosis. This study addresses the role of CD117 in canine mast cell tumours by studying the correlations between CD117 immunoexpression patterns, two proliferation markers (Ki67 and AgNORs) histological grade, and several other pathological variables.
Results
Highly significant (p < 0,001) correlations were found between CD117 immunostaining patterns and histological grade, cell proliferation markers (Ki67, AgNORs) and tumoral necrosis. Highly significant (p < 0,001) correlations were also established between the two cellular proliferation markers and histological grade, tumour necrosis and epidermal ulceration. A significant correlation (p = 0.035) was observed between CD117 expression patterns and epidermal ulceration. No differences were observed between focal and diffuse cytoplasmic CD117 staining patterns concerning any of the variables studied.
Conclusion
These findings highlight the key role of CD117 in the biopathology of canine MCTs and confirm the relationship between aberrant CD117 expression and increased cell proliferation and higher histological grade. Further studies are needed to unravel the cellular mechanisms underlying focal and diffuse cytoplasmic CD117 staining patterns, and their respective biopathologic relevance.
doi:10.1186/1746-6148-3-19
PMCID: PMC2077863  PMID: 17711582
24.  Balanced activity in basal ganglia projection pathways is critical for contraversive movements 
Nature Communications  2014;5:4315.
The basal ganglia, and the striatum in particular, have been implicated in the generation of contraversive movements. The striatum projects to downstream basal ganglia nuclei through two main circuits, originating in striatonigral and striatopallidal neurons, and different models postulate that the two pathways can work in opposition or synergistically. Here we show striatonigral and striatopallidal neurons are concurrently active during spontaneous contraversive movements. Furthermore, we show that unilateral optogenetic inhibition of either or both projection pathways disrupts contraversive movements. Consistently, simultaneous activation of both neuron types produces contraversive movements. Still, we also show that imbalanced activity between the pathways can result in opposing movements being driven by each projection pathway. These data show that balanced activity in both striatal projection pathways is critical for the generation of contraversive movements and highlights that imbalanced activity between the two projection pathways can result in opposing motor output.
The striatum is required for evoking contraversive movements from each brain hemisphere, but it is unclear how. Here, Tecuapetla et al. use optogenetics to inhibit direct and indirect downstream striatal projection pathways, and show that activity in both pathways is necessary for contraversive movements.
doi:10.1038/ncomms5315
PMCID: PMC4102112  PMID: 25002180

Results 1-24 (24)