A novel apparatus/protocol designed for optogenetic manipulation and recording of individual neurons during a motivation and working memory task in the rodent

Innovative molecular tools allow neuroscientists to study neural circuitry associated with specific behaviors. Consequently, behavioral methods must be developed to interface with these new molecular tools in order for neuroscientists to identify the causal elements underlying behavior and decision-making processes. Here we present an apparatus and protocol for a novel Go/No-Go behavioral paradigm to study the brain attention and motivation/reward circuitry in awake, head-restrained rodents. This experimental setup allows: (1) Painless and stable restraint of the head and body; (2) Rapid acquisition to simple or complex operant tasks; (3) Repeated electrophysiological single and multiple unit recordings during ongoing behavior; (4) Pharmacological and viral manipulation of various brain regions via targeted guide cannula, and; (5) Optogenetic cell-type specific activation and silencing with simultaneous electrophysiological recording. In addition to the experimental advantages, the head-restraint system is relatively inexpensive and training parameters can be easily modulated to the specifications of the experimenter. The system runs on custom LabView software. In summary, our novel apparatus and protocol allows researchers to study and manipulate components of behavior, such as motivation, impulsivity, and reward-related working memory during an ongoing operant behavioral task without interference from non task-related behaviors. For more information on the custom apparatus, software or to collaborate please visit www.neuro-cloud.net/nature-precedings/dolzani

Behavioural and physiological correlates of impulsivity in the domestic dog (Canis familiaris)

Impulsivity is a trait related to inhibitory control which is expressed in a range of behaviours. Impulsive individuals show a decreased ability to tolerate delay of reinforcement, and more impulsive behaviour has been linked to decreased levels of serotonin and dopamine in a number of species. In domestic dogs, impulsivity is implicated in problem behaviours that result from a lack of self control, but currently there are no published studies that assess behavioural and physiological measures of impulsivity in relation to this trait. Impulsivity scores were calculated for 41 dogs using an owner-report assessment, the Dog Impulsivity Assessment Scale (DIAS). Twenty-three of these subjects completed an operant choice task based on a delayed reward paradigm, to assess their tolerance to delay of reinforcement. High Pressure Liquid Chromatography (HPLC) with Fluorometric Detection was used to detect levels of the metabolites of serotonin (5-HIAA) and dopamine (HVA) in the urine of 17 of the subjects. Higher impulsivity scores were found to be significantly correlated with more impulsive behaviour (reduced tolerance to delay of reinforcement) in the behaviour tests and lower levels of urinary 5-HIAA and 5-HIAA/HVA ratio. The results demonstrate convergent validity between impulsivity (as assessed by the DIAS) and behavioural and physiological parameters

Learning spatial aversion is sensory-specific in the hematophagous insect Rhodnius prolixus

Even though innate behaviors are essential for assuring quick responses to expected stimuli, experience-dependent behavioral plasticity confers an advantage when unexpected conditions arise. As being rigidly responsive to too many stimuli can be biologically expensive, adapting preferences to time-dependent relevant environmental conditions provide a cheaper and wider behavioral reactivity. According to their specific life habits, animals prioritize different sensory modalities to maximize environment exploitation. Besides, when mediating learning processes, the salience of a stimulus usually plays a relevant role in determining the intensity of an association. Then, sensory prioritization might reflect an heterogeneity in the cognitive abilities of an individual. Here, we analyze in the kissing bug Rhodnius prolixus if stimuli from different sensory modalities generate different cognitive capacities under an operant aversive paradigm. In a 2-choice walking arena, by registering the spatial distribution of insects over an experimental arena, we evaluated firstly the innate responses of bugs confronted to mechanical (rough substrate), visual (green light), thermal (32°C heated plate), hygric (humidified substrate), gustatory (sodium chloride), and olfactory (isobutyric acid) stimuli. In further experimental series bugs were submitted to an aversive operant conditioning by pairing each stimulus with a negative reinforcement. Subsequent tests allowed us to analyze if the innate behaviors were modulated by such previous aversive experience. In our experimental setup mechanical and visual stimuli were neutral, the thermal cue was attractive, and the hygric, gustatory and olfactory ones were innately aversive. After the aversive conditioning, responses to the mechanical, the visual, the hygric and the gustatory stimuli were modulated while responses to the thermal and the olfactory stimuli remained rigid. We present evidences that the spatial learning capacities of R. prolixus are dependent on the sensory modality of the conditioned stimulus, regardless their innate valence (i.e., neutral, attractive, or aversive). These differences might be given by the biological relevance of the stimuli and/or by evolutionary aspects of the life traits of this hematophagous insect.Fil: Minoli, Sebastian. Universidad de Buenos Aires; ArgentinaFil: Cano, Agustina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Pontes, Gina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Magallanes, Amorina. Universidad de Buenos Aires; ArgentinaFil: Roldán, Nahuel. Universidad de Buenos Aires; ArgentinaFil: Barrozo, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

A Mechanism Linking Two Known Vulnerability Factors for Alcohol Abuse: Heightened Alcohol Stimulation and Low Striatal Dopamine D2 Receptors

Alcohol produces both stimulant and sedative effects in humans and rodents. In humans, alcohol abuse disorder is associated with a higher stimulant and lower sedative responses to alcohol. Here, we show that this association is conserved in mice and demonstrate a causal link with another liability factor: low expression of striatal dopamine D2 receptors (D2Rs). Using transgenic mouse lines, we find that the selective loss of D2Rs on striatal medium spiny neurons enhances sensitivity to ethanol stimulation and generates resilience to ethanol sedation. These mice also display higher preference and escalation of ethanol drinking, which continues despite adverse outcomes. We find that striatal D1R activation is required for ethanol stimulation and that this signaling is enhanced in mice with low striatal D2Rs. These data demonstrate a link between two vulnerability factors for alcohol abuse and offer evidence for a mechanism in which low striatal D2Rs trigger D1R hypersensitivity, ultimately leading to compulsive-like drinkingFil: Bocarsly, Miriam E.. National Institutes of Health; Estados UnidosFil: da Silva e Silva, Daniel. National Institutes of Health; Estados UnidosFil: Kolb, Vanessa. National Institutes of Health; Estados UnidosFil: Luderman, Kathryn D.. National Institutes of Health; Estados UnidosFil: Shashikiran, Sannidhi. National Institutes of Health; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Sibley, David R.. National Institutes of Health; Estados UnidosFil: Dobbs, Lauren K.. National Institutes of Health; Estados Unidos. University of Texas at Austin; Estados UnidosFil: Álvarez, Verónica Alicia. National Institutes of Health; Estados Unido

Speech and language therapy for aphasia following stroke

Background  Aphasia is an acquired language impairment following brain damage that affects some or all language modalities: expression and understanding of speech, reading, and writing. Approximately one third of people who have a stroke experience aphasia.  Objectives  To assess the effects of speech and language therapy (SLT) for aphasia following stroke.  Search methods  We searched the Cochrane Stroke Group Trials Register (last searched 9 September 2015), CENTRAL (2015, Issue 5) and other Cochrane Library Databases (CDSR, DARE, HTA, to 22 September 2015), MEDLINE (1946 to September 2015), EMBASE (1980 to September 2015), CINAHL (1982 to September 2015), AMED (1985 to September 2015), LLBA (1973 to September 2015), and SpeechBITE (2008 to September 2015). We also searched major trials registers for ongoing trials including ClinicalTrials.gov (to 21 September 2015), the Stroke Trials Registry (to 21 September 2015), Current Controlled Trials (to 22 September 2015), and WHO ICTRP (to 22 September 2015). In an effort to identify further published, unpublished, and ongoing trials we also handsearched theInternational Journal of Language and Communication Disorders(1969 to 2005) and reference lists of relevant articles, and we contacted academic institutions and other researchers. There were no language restrictions.  Selection criteria  Randomised controlled trials (RCTs) comparing SLT (a formal intervention that aims to improve language and communication abilities, activity and participation) versus no SLT; social support or stimulation (an intervention that provides social support and communication stimulation but does not include targeted therapeutic interventions); or another SLT intervention (differing in duration, intensity, frequency, intervention methodology or theoretical approach).  Data collection and analysis  We independently extracted the data and assessed the quality of included trials. We sought missing data from investigators.  Main results  We included 57 RCTs (74 randomised comparisons) involving 3002 participants in this review (some appearing in more than one comparison). Twenty-seven randomised comparisons (1620 participants) assessed SLT versus no SLT; SLT resulted in clinically and statistically significant benefits to patients' functional communication (standardised mean difference (SMD) 0.28, 95% confidence interval (CI) 0.06 to 0.49, P = 0.01), reading, writing, and expressive language, but (based on smaller numbers) benefits were not evident at follow-up. Nine randomised comparisons (447 participants) assessed SLT with social support and stimulation; meta-analyses found no evidence of a difference in functional communication, but more participants withdrew from social support interventions than SLT. Thirty-eight randomised comparisons (1242 participants) assessed two approaches to SLT. Functional communication was significantly better in people with aphasia that received therapy at a high intensity, high dose, or over a long duration compared to those that received therapy at a lower intensity, lower dose, or over a shorter period of time. The benefits of a high intensity or a high dose of SLT were confounded by a significantly higher dropout rate in these intervention groups. Generally, trials randomised small numbers of participants across a range of characteristics (age, time since stroke, and severity profiles), interventions, and outcomes.  Authors' conclusions  Our review provides evidence of the effectiveness of SLT for people with aphasia following stroke in terms of improved functional communication, reading, writing, and expressive language compared with no therapy. There is some indication that therapy at high intensity, high dose or over a longer period may be beneficial. HIgh-intensity and high dose interventions may not be acceptable to all

DNMT3a in the hippocampal CA1 is crucial in the acquisition of morphine self‐administration in rats

Drug‐reinforced excessive operant responding is one fundamental feature of long-lasting addiction‐like behaviors and relapse in animals. However, the transcriptional regulatory mechanisms responsible for the persistent drug‐specific (not natural rewards) operant behavior are not entirely clear. In this study, we demonstrate a key role for one of the de novo DNA methyltransferase, DNMT3a, in the acquisition of morphine self‐administration (SA) in rats. The expression of DNMT3a in the hippocampal CA1 region but not in the nucleus accumbens shell was significantly up‐regulated after 1‐ and 7‐day morphine SA (0.3 mg/kg/infusion) but not after the yoked morphine injection. On the other hand, saccharin SA did not affect the expression of DNMT3a or DNMT3b. DNMT inhibitor 5‐aza‐2‐deoxycytidine (5‐aza) microinjected into the hippocampal CA1 significantly attenuated the acquisition of morphine SA. Knockdown of DNMT3a also impaired the ability to acquire the morphine SA. Overall, these findings suggest that DNMT3a in the hippocampus plays an important role in the acquisition of morphine SA and may be a valid target to prevent the development of morphine addiction. Includes Supplemental informatio

Acute drug effects on habitual and non-habitual responding in crossed high alcohol preferring mice

RATIONALE: Drug reward plays a central role in acquiring drug-seeking behavior. However, subjects may continue using drugs despite negative consequences because self-administration becomes habitual, and divorced from outcome values. Although a history of drug and alcohol use expedite habit acquisition, and in spite of the fact that self-administration leads to intoxication, the acute effects of drugs on habitual responding are not well understood. OBJECTIVES: We sought to observe how acute ethanol and amphetamine affect the balance between habitual and goal-directed behavior, as measured by a fluid-reinforced operant conditioning task. METHODS: Selectively bred crossed high-alcohol-preferring (cHAP) mice were trained on an operant conditioning task reinforced on a variable interval schedule with 1% banana solution, which was subsequently devalued via LiCl pairing in half the animals. Ethanol (1.0 g/kg), amphetamine (2.0 mg/kg), or saline was administered prior to a post-devaluation test. RESULTS: Overall, mice showed habitual behavior, but when divided into high- or low-responding groups based on training response rates, saline-treated, low-responding animals devalued, while saline-treated high-responding animals did not. Furthermore, amphetamine elicited devaluation even in high-responding animals, while ethanol prevented devaluation even in low-responding animals. CONCLUSIONS: These data show that ethanol shifts animals toward behaving habitually. This may illuminate why alcohol-intoxicated individuals display impaired judgment about the relative merits of drinking, and potentially serve as a mechanism by which intoxicated subjects resume previously devalued behaviors, such as comorbid drug use. These findings also show that high variable interval response rates facilitate a shift from goal-directed to habitual behavior

Behavioral Phenotyping of Dopamine Transporter Knockout Rats: Compulsive Traits, Motor Stereotypies, and Anhedonia

Alterations in dopamine neurotransmission are generally associated with diseases such as attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Such diseases typically feature poor decision making and lack of control on executive functions and have been studied through the years using many animal models. Dopamine transporter (DAT) knockout (KO) and heterozygous (HET) mice, in particular, have been widely used to study ADHD. Recently, a strain of DAT KO rats has been developed (1). Here, we provide a phenotypic characterization of reward sensitivity and compulsive choice by adult rats born from DAT-HET dams bred with DAT-HET males, in order to further validate DAT KO rats as an animal model for preclinical research. We first tested DAT KO rats' sensitivity to rewarding stimuli, provided by highly appetitive food or sweet water; then, we tested their choice behavior with an Intolerance-to-Delay Task (IDT). During these tests, DAT KO rats appeared less sensitive to rewarding stimuli than wild-type (WT) and HET rats: they also showed a prominent hyperactive behavior with a rigid choice pattern and a wide number of compulsive stereotypies. Moreover, during the IDT, we tested the effects of amphetamine (AMPH) and RO-5203648, a trace amine-associated receptor 1 (TAAR1) partial agonist. AMPH accentuated impulsive behaviors in WT and HET rats, while it had no effect in DAT KO rats. Finally, we measured the levels of tyrosine hydroxylase, dopamine receptor 2 (D2), serotonin transporter, and TAAR1 mRNA transcripts in samples of ventral striatum, finding no significant differences between WT and KO genotypes. Throughout this study, DAT KO rats showed alterations in decision-making processes and in motivational states, as well as prominent motor and oral stereotypies: more studies are warranted to fully characterize and efficiently use them in preclinical research

Intra-accumbens baclofen, but not muscimol, increases second order instrumental responding for food reward in rats

Stimulation of either GABA(A) or GABA(B) receptors within the nucleus accumbens shell strongly enhances food intake in rats. However the effects of subtype-selective stimulation of GABA receptors on instrumental responses for food reward are less well characterized. Here we contrast the effects of the GABA(A) receptor agonist muscimol and GABA(B) receptor agonist baclofen on instrumental responding for food using a second order reinforcement schedule. Bilateral intra-accumbens administration of baclofen (220-440 pmol) stimulated responding but a higher dose (660 pmol) induced stereotyped oral behaviour that interfered with responding. Baclofen (220-660 pmol) also stimulated intake of freely available chow. Muscimol (220-660 pmol) was without effect on responding for food on this schedule but did stimulate intake of freely available chow. Unilateral administration of either baclofen or muscimol (220 pmol) induced similar patterns of c-fos immunoreactivity in several hypothalamic sites but differed in its induction in the central nucleus of the amygdala. We conclude that stimulation of GABA(A) or GABA(B) receptors in the nucleus accumbens shell of rats produces clearly distinguishable effects on operant responding for food

5-HT6R Viral Vector-Mediated Indirect Pathway Activation in the Dorsolateral Striatum: A Discussion on Basal Ganglia Habitual and Goal-Directed Circuits

Altering maladaptive behavioral tendencies is relevant for clinical interventions, making research on underlying mechanisms of habit essential. Mechanisms of habit are explored here with differential activation of the indirect pathway in the basal ganglia. Viral vector-mediated overexpression of the 5-hydroxytryptamine 6 (5-HT6) receptor in the indirect pathway of the dorsolateral striatum was used to increase indirect pathway activity. Subjects were trained such that control animals were expected to exhibit habitual behavior. We hypothesized increased activation of the indirect pathway would maintain goal-directed behavior. To test this hypothesis female rats were assigned to 5-HT6 receptor upregulation or control groups in a reward devaluation behavior paradigm to assess habitual behavior. Although our results do not show anticipated behavioral results following reward devaluation, a lack of statistical power due to small sample sizes does not allow conclusions to be reached