RESUMO
Demand theory can be applied to analyze how animal consumers change their selection of commodities in response to changes in commodity prices, given budget constraints. Previous work has shown that demand elasticities in rats differed between uncompensated budget conditions in which the budget available to be spent on the commodities (e.g., the finite number of discrete operants to "purchase" rewards in two-alternative fixed-ratio schedules) was kept constant, and compensated budget conditions in which the budget was adjusted so that consumers could potentially continue to obtain the original reward bundles. Here, we hypothesized that rat anterior cingulate cortex (ACC) was necessary to produce this budget effect on demand elasticities. We applied excitotoxic or sham lesions to ACC in rats performing an effort task in which the prices of liquid vanilla or chocolate rewards (the effort required to obtain rewards) and the budget (the total number of operants) was manipulated. When reward prices changed, and the budget was compensated, all rats adjusted their demand for chocolate and vanilla accordingly. In sham-lesioned rats, changes in demand were even more pronounced when the budget was not compensated for the price changes. By contrast, ACC-lesioned animals did not show this additional budget effect. An in-depth comparison of the rats' choice patterns showed that, unlike sham rats, ACC-lesioned animals failed to maximize session-bundle utility after price/budget changes, revealing deficits in higher-order choice-strategy adaptations. Our results suggest a novel role of ACC in considering purchasing power during complex cost-benefit value computations.SIGNIFICANCE STATEMENT Anterior cingulate cortex (ACC) is important for allocating effort in cost-benefit calculations in animals and humans. Economic theory prescribes that the value of the costs in cost-benefit analyses not only depends on the net nominal costs required to purchase a reward, but also on the available budget resources, i.e., on the budget's "purchasing value." We asked whether ACC, a region implicated in effort-based decision-making and reward comparisons, is required for computing the value of effort relative to a budget constraint. Applying demand theory to describe rat choices in a rodent effort allocation task with varying effort prices and budgets, we show that ACC integrity was necessary for computing purchasing power, a core variable in economic choice theory.
Assuntos
Comportamento de Escolha/fisiologia , Giro do Cíngulo/fisiologia , Recompensa , Animais , Comportamento Animal/fisiologia , Masculino , Ratos , Ratos Long-EvansRESUMO
Rats adapt their food choices to conform to their conspecifics' dietary preferences. The nucleus accumbens shell is a relevant brain region to process reward-related and motivated behaviours and social information. Here, we hypothesize that the integrity of the nucleus accumbens shell is necessary to show socially transmitted food preferences. We made excitotoxic and sham lesions of nucleus accumbens shell in male Long-Evans rats who performed a social transmission of food preference task. In this task, observer rats revealed their original preference for one out of two food options. Afterward, they were exposed to a demonstrator rat who was fed with the observer's originally non-preferred food, and the observer's food choices were sampled again. Sham lesioned observer rats changed their food preferences following interaction with the demonstrator, specifically by increasing the intake of their originally non-preferred food type. This interaction-related change in preference was not found after nucleus accumbens shell lesions. The lesion effects on choice were not the consequence of impaired social or non-social motivation, anxiety or sensory or motor function, suggesting that they reflected a genuine deficit in social reward revaluation. These results highlight the role of nucleus accumbens shell in revaluating food rewards to match a conspecific's preferences.
Assuntos
Preferências Alimentares , Núcleo Accumbens , Ratos , Masculino , Animais , Ratos Long-Evans , Recompensa , MotivaçãoRESUMO
Despite amyloid plaques, consisting of insoluble, aggregated amyloid-ß peptides, being a defining feature of Alzheimer's disease, their significance has been challenged due to controversial findings regarding the correlation of cognitive impairment in Alzheimer's disease with plaque load. The amyloid cascade hypothesis defines soluble amyloid-ß oligomers, consisting of multiple amyloid-ß monomers, as precursors of insoluble amyloid-ß plaques. Dissecting the biological effects of single amyloid-ß oligomers, for example of amyloid-ß dimers, an abundant amyloid-ß oligomer associated with clinical progression of Alzheimer's disease, has been difficult due to the inability to control the kinetics of amyloid-ß multimerization. For investigating the biological effects of amyloid-ß dimers, we stabilized amyloid-ß dimers by an intermolecular disulphide bridge via a cysteine mutation in the amyloid-ß peptide (Aß-S8C) of the amyloid precursor protein. This construct was expressed as a recombinant protein in cells and in a novel transgenic mouse, termed tgDimer mouse. This mouse formed constant levels of highly synaptotoxic soluble amyloid-ß dimers, but not monomers, amyloid-ß plaques or insoluble amyloid-ß during its lifespan. Accordingly, neither signs of neuroinflammation, tau hyperphosphorylation or cell death were observed. Nevertheless, these tgDimer mice did exhibit deficits in hippocampal long-term potentiation and age-related impairments in learning and memory, similar to what was observed in classical Alzheimer's disease mouse models. Although the amyloid-ß dimers were unable to initiate the formation of insoluble amyloid-ß aggregates in tgDimer mice, after crossbreeding tgDimer mice with the CRND8 mouse, an amyloid-ß plaque generating mouse model, Aß-S8C dimers were sequestered into amyloid-ß plaques, suggesting that amyloid-ß plaques incorporate neurotoxic amyloid-ß dimers that by themselves are unable to self-assemble. Our results suggest that within the fine interplay between different amyloid-ß species, amyloid-ß dimer neurotoxic signalling, in the absence of amyloid-ß plaque pathology, may be involved in causing early deficits in synaptic plasticity, learning and memory that accompany Alzheimer's disease.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Transtornos Cognitivos/metabolismo , Plasticidade Neuronal/fisiologia , Placa Amiloide/metabolismo , Multimerização Proteica/fisiologia , Peptídeos beta-Amiloides/genética , Animais , Transtornos Cognitivos/genética , Transtornos Cognitivos/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Placa Amiloide/genética , Placa Amiloide/patologiaRESUMO
In a recent study, we demonstrated that rats prefer mutual rewards in a Prosocial Choice Task. Here, employing the same task, we show that the integrity of basolateral amygdala was necessary for the expression of mutual reward preferences. Actor rats received bilateral excitotoxic (n=12) or sham lesions (n=10) targeting the basolateral amygdala and were subsequently tested in a Prosocial Choice Task where they could decide between rewarding ("Both Reward") or not rewarding a partner rat ("Own Reward"), either choice yielding identical reward to the actors themselves. To manipulate the social context and control for secondary reinforcement sources, actor rats were paired with either a partner rat (partner condition) or with an inanimate rat toy (toy condition). Sham-operated animals revealed a significant preference for the Both-Reward-option in the partner condition, but not in the toy condition. Amygdala-lesioned animals exhibited significantly lower Both-Reward preferences than the sham group in the partner but not in the toy condition, suggesting that basolateral amygdala was required for the expression of mutual reward preferences. Critically, in a reward magnitude discrimination task in the same experimental setup, both sham-operated and amygdala-lesioned animals preferred large over small rewards, suggesting that amygdala lesion effects were restricted to decision making in social contexts, leaving self-oriented behavior unaffected.
Assuntos
Complexo Nuclear Basolateral da Amígdala/fisiologia , Comportamento de Escolha/fisiologia , Recompensa , Comportamento Social , Animais , Masculino , Ratos , Ratos Long-EvansRESUMO
Impaired learning and memory performance is often found in aging as an early sign of dementia. It is associated with neuronal loss and reduced functioning of cholinergic networks. Here we present evidence that the neurokinin3 receptors (NK3-R) and their influence on acetylcholine (ACh) release may represent a crucial mechanism that underlies age-related deficits in learning and memory. Repeated pharmacological stimulation of NK3-R in aged rats was found to improve learning in the water maze and in object-place recognition. This treatment also enhanced in vivo acetylcholinergic activity in the frontal cortex, hippocampus, and amygdala but reduced NK3-R mRNA expression in the hippocampus. Furthermore, NK3-R agonism incurred a significantly higher increase in ACh levels in aged animals that showed superior learning than in those that were most deficient in learning. Our findings suggest that the induced activation of ACh, rather than basal ACh activity, is associated with superior learning in the aged. To test whether natural variation in NK3-R function also determines learning and memory performance in aged humans, we investigated 209 elderly patients with cognitive impairments. We found that of the 15 analyzed single single-nucleotide ploymorphism (SNPs) of the NK3-R-coding gene, TACR3, the rs2765 SNP predicted the degree of impairment of learning and memory in these patients. This relationship could be partially explained by a reduced right hippocampus volume in a subsample of 111 tested dementia patients. These data indicate the NK3-R as an important target to predict and improve learning and memory performance in the aged organism.
Assuntos
Envelhecimento/fisiologia , Envelhecimento/psicologia , Transtornos Cognitivos/fisiopatologia , Aprendizagem/fisiologia , Memória/fisiologia , Receptores da Neurocinina-3/fisiologia , Acetilcolina/fisiologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Animais , Transtornos Cognitivos/genética , Transtornos Cognitivos/psicologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Demência/genética , Demência/fisiopatologia , Demência/psicologia , Feminino , Estudos de Associação Genética , Humanos , Aprendizagem/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Pessoa de Meia-Idade , Modelos Animais , Modelos Neurológicos , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Receptores da Neurocinina-3/agonistas , Receptores da Neurocinina-3/genéticaRESUMO
Patients diagnosed with neuropsychiatric disorders, such as autism and schizophrenia, suffer from disorganized speech. The disrupted-in-schizophrenia 1 (DISC1) protein pathway is considered a risk factor for the development of several psychiatric disorders and plays an important role in the dysregulation of dopamine (DA), which in turn plays an important role in the regulation of ultrasonic vocalizations (USVs) in rats. Moreover, the DISC1 protein pathway has been identified as a cause of social anhedonia, that is, a decrease in the drive for social interactions. USVs transmit specific affective information to other rats, with 50-kHz calls indicating a positive affective state in rats. Dysregulation of the dopaminergic system impacts the qualitative and quantitative features of USVs, such as duration, peak frequency, and the call rate. In this study, we thus used a well-established transgenic DISC1 (tgDISC1) rat line to investigate whether the neural (decreased DA levels in the dorsal striatum, amygdala, and hippocampus (HPC)) and behavioral (social anhedonia) features of tgDISC1 rats could be manifested through the modulation of their 50-kHz USVs. Analyses of three features (call rate, duration, and peak frequency) of all 50-kHz revealed no significant differences between groups, suggesting decreased DA levels in the dorsal striatum and amygdala, and HPC may affect social interaction but leave 50-kHz USV production intact.
Assuntos
Ultrassom , Vocalização Animal , Ratos , Animais , Ratos Transgênicos , Vocalização Animal/fisiologia , Anedonia , Emoções , Dopamina/metabolismo , Proteínas do Tecido NervosoRESUMO
The neurokinin receptors (NK-R), NK(2)- and NK(3)-R, have been implicated in behavioral processes, but apparently in opposite ways: while NK(2)-R agonism disrupts memory and has anxiogenic-like action, NK(3) -R agonists facilitate memory and display anxiolytic-like effects. Systemic application of NK(2)-R antagonists block the release of acetylcholine (ACh) in the hippocampus, which is induced by intraseptal administration of the NK(2)-R ligand, neurokinin A (NKA). We investigated the effects of medial septal injection of NKA and a preferred ligand of NK(3)-R, neurokinin B (NKB), on the activity of cholinergic neurons of the basal forebrain and assessed the role of the medial septal NK(2)-R in the control of extracellular ACh levels in cholinergic projection areas. ACh was dialysed in the frontal cortex, amygdala and hippocampus of anesthetized animals and was analysed by HPLC-EC. ACh levels in hippocampus and amygdala, but not in frontal cortex were increased after intraseptal injection of either NKA or NKB (0.1, 1, 10 µM). Application of the nonpeptidic NK(2)-R antagonist, saredutant SR48968 (1, 10, 100 pM), followed by NKA (1 µM) or NKB (10 µM) injection into the medial septum, blocked the ACh increase in hippocampus and amygdala. These results indicate that medial septal NK(2)-R have an important role in mediating ACh release, for one, via the septal-hippocampal cholinergic projection and, secondly, via direct or indirect route to the amygdala, but not frontal cortex. They also support the hypothesis that hippocampal cholinergic neurotransmission controls amygdala function suggesting that this interaction is regulated via NK(2)-R in the medial septum.
Assuntos
Acetilcolina/metabolismo , Tonsila do Cerebelo/metabolismo , Hipocampo/metabolismo , Neurocinina A/metabolismo , Neurocinina B/metabolismo , Receptores da Neurocinina-2/metabolismo , Análise de Variância , Animais , Benzamidas/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Lobo Frontal/metabolismo , Masculino , Memória/efeitos dos fármacos , Neurocinina A/administração & dosagem , Neurocinina B/administração & dosagem , Piperidinas/farmacologia , Ratos , Ratos Wistar , Receptores da Neurocinina-2/agonistas , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-3/agonistas , Receptores da Neurocinina-3/antagonistas & inibidores , Receptores da Neurocinina-3/metabolismo , Núcleos Septais/metabolismo , Septo do Cérebro/metabolismoRESUMO
Senktide, a potent neurokinin-3 receptor (NK3-R) agonist, increases acetylcholine (ACh) release in the striatum, the prefrontal cortex (Schäble et al., 2011), the amygdala and hippocampus, presumably via postsynaptic mechanisms. A promnestic action of NK3-R agonists has been described in a variety of learning/memory tasks. The memory-enhancing effects of NK3-R agonists and their activating influence on ACh suggest a possible role of the NK3-R in learning and memory via cholinergic modulation. Deterioration of the cholinergic system in the basal forebrain has been associated with learning and memory deficits and cholinergic agents have promnestic effects in a variety of learning paradigms. The anticholinergic drug, scopolamine, a muscarinic ACh receptor antagonist, incurs deficits in a variety of learning tasks and provides a useful tool to investigate the role of the cholinergic systems in mechanisms underlying learning and memory. The aim of this study was to ascertain the effect of the NK3-R agonist, senktide, in the scopolamine-induced deficit model. We hypothesized that senktide treatment would attenuate scopolamine-induced (subcutaneous--s.c. 0.75 mg/kg) memory impairment in three novelty preference paradigms based on spontaneous object exploration: namely object recognition, object-place recognition and object recognition for temporal order. Administration of senktide reversed the scopolamine-induced memory deficits by re-establishing object recognition (s.c. 0.2 mg/kg), object-place recognition (0.2 and 0.4 mg/kg), as well as object recognition for temporal order (0.4 mg/kg) in adult Wistar rats. These results indicate memory enhancing effects of senktide in animals subjected to scopolamine-induced memory impairments and indicate that the promnestic action of NK3-R agonists is mediated by muscarinic cholinergic mechanisms.
Assuntos
Transtornos da Memória/tratamento farmacológico , Memória/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Receptores da Neurocinina-3/agonistas , Substância P/análogos & derivados , Animais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Fragmentos de Peptídeos/uso terapêutico , Ratos , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Escopolamina , Substância P/farmacologia , Substância P/uso terapêuticoRESUMO
Temporal reward discounting describes the decrease of value of a reward as a function of delay. Decision-making between future aversive outcomes is much less studied, and there is no clear decision pattern across studies; while some authors suggest that human and nonhuman animals prefer sooner over later painful shocks, others found the exact opposite. In a series of three experiments, Long-Evans rats chose between differently timed electric shocks and rewards in a T-maze. In experiment 1, rats chose between early and late painful shocks with identical, long reward delays; in experiment 2, they chose between early reward and early shocks, or late rewards and late shocks; in experiment 3, they chose between early and late rewards, with identical, short delays to the shock. We tested the predictions of two competing hypotheses: the aversive discounting theory assumes that future shocks are discounted, and, hence, less unpleasant than early shocks. The utility from anticipation theory implies that rats derive negative utility from waiting for the shock; late shocks should, hence, be more unpleasant than early shocks. We did not find unanimous evidence for either theory. Instead, our results are more consistent with the post hoc idea that shocks may have negative spill-over effects on reward values, the closer in time a shock is to a subsequent reward, the stronger the reward is devalued. Interestingly and consistent with our theory, we find that, depending on the temporal shock-reward contiguity, rats can be brought to prefer later over sooner rewards of identical magnitudes.
Assuntos
Desvalorização pelo Atraso , Punição , Humanos , Ratos , Animais , Ratos Long-Evans , Recompensa , Afeto , DorRESUMO
Deficits in social interaction or social cognition are key phenotypes in a variety of chronic mental diseases, yet, their modeling and molecular dissection are only in their infancy. The Disrupted-in-Schizophrenia 1 (DISC1) signaling pathway is considered to play a role in different psychiatric disorders such as schizophrenia, depression, and biopolar disorders. DISC1 is involved in regulating the dopaminergic neurotransmission in, among others, the mesolimbic reward system. A transgenic rat line tgDISC1 has been introduced as a model system to study behavioral phenotypes associated with abnormal DISC1 signaling pathways. Here, we evaluated the impact of impaired DISC1 signaling on social (social interaction) and non-social (sucrose) reward preferences in the tgDISC1 animal model. In a plus-maze setting, rats chose between the opportunity for social interaction with an unfamiliar juvenile conspecific (social reward) or drinking sweet solutions with variable sucrose concentrations (non-social reward). tgDISC1 rats differed from wild-type rats in their social, but not in their non-social reward preferences. Specifically, DISC1 rats showed a lower interest in interaction with the juvenile conspecific, but did not differ from wild-type rats in their preference for higher sucrose concentrations. These results suggest that disruptions of the DISC1 signaling pathway that is associated with altered dopamine transmission in the brain result in selective deficits in social motivation reminiscent of phenotypes seen in neuropsychiatric illness.
Assuntos
Anedonia , Proteínas do Tecido Nervoso/metabolismo , Anedonia/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Fenótipo , Ratos , Esquizofrenia/genética , Esquizofrenia/metabolismo , SacaroseRESUMO
A growing body of evidence supports the hypothesis that juvenile cognitive training shapes neural networks and behavior, and thereby determines the adult's capacity for learning and memory. In particular, we have shown that infant rats, even though they do not develop an active avoidance strategy in a two-way active avoidance task, show as adults accelerated learning in the same learning task. This indicates that a memory trace was formed in the infant rats, which most likely is recruited during adult training. To identify the learning conditions, which are essential prerequisites to form this memory trace in infancy or adolescence, we investigated the critical impact of: (i) age, (ii) CS-UCS contingency, and (iii) pre-training intensity on this facilitating effect. We observed: (i) an age-dependent improvement of avoidance learning, (ii) that the beneficial impact of infant or adolescent pre-training on adult learning increases with the age at pre-training, (iii) that CS-UCS contingency during infant pre-training was most efficient to accelerate adult learning, (iv) that pre-training intensity (i.e. number of pre-training trials) was positively correlated with the pre-training induced acceleration of adult learning, and (v) that infant rats, compared to adolescent rats, need a higher training intensity to show learning improvement as adults. These results indicate that infant rats develop a goal-oriented escape strategy, which during adult training is replaced by an avoidance strategy, facilitated by the recruitment of the CS-UCS association, which has been learned during infant training. Based on these results the future challenge will be to identify the specific contribution of prefronto-limbic circuits in infant and adult learning in relation to their functional maturation.
Assuntos
Aprendizagem por Associação/fisiologia , Aprendizagem da Esquiva/fisiologia , Condicionamento Psicológico/fisiologia , Fatores Etários , Análise de Variância , Animais , Feminino , Ratos , Ratos WistarRESUMO
Rats show mutual-reward preferences, i.e., they prefer options that result in a reward for both themselves and a conspecific partner to options that result in a reward for themselves, but not for the partner. In a previous study, we have shown that lesions of the basolateral amygdala (BLA) reduced choices for mutual rewards. Here, we aimed to explore the role of 5-HT1A receptors within the BLA in mutual-reward choices. Rats received daily injections of either 50 or 25 ng of the 5-HT1A receptor agonist 8-OH-DPAT or a vehicle solution into the BLA and mutual-reward choices were measured in a rodent prosocial choice task. Compared to vehicle injections, 8-OH-DPAT significantly increased mutual-reward choices when a conspecific was present. By contrast, mutual-reward choices were significantly reduced by 8-OH-DPAT injections in the presence of a toy rat. The effect of 8-OH-DPAT injections was statistically significant during the expression, but not during learning of mutual-reward behavior, although an influence of 8-OH-DPAT injections on learning could not be excluded. There were no differences between 8-OH-DPAT-treated and vehicle-treated rats in general reward learning, behavioral flexibility, locomotion or anxiety. In this study, we have shown that repeated injections of the 5-HT1A receptor agonist 8-OH-DPAT have the potential to increase mutual-reward choices in a social setting without affecting other behavioral parameters.
Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiologia , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Receptor 5-HT1A de Serotonina/fisiologia , Recompensa , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , 8-Hidroxi-2-(di-n-propilamino)tetralina/administração & dosagem , Animais , Ansiedade , Injeções , Locomoção/efeitos dos fármacos , Ratos , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Comportamento SocialRESUMO
Rats emit vocalizations in the ultrasonic range (ultrasonic vocalizations; USVs), of which 50-kHz USVs could communicate positive affective states and induce approach behavior in conspecifics, whereas 22-kHz USVs might signal negative affective states and potential threats. Listening to 50-kHz USVs can be rewarding, but it is unknown which brain mechanisms are responsible for the assignment of reinforcing value to 50-kHz USVs . The behavioral responses induced by listening to 22-kHz USVs are heterogeneous and need further characterization. The amygdala is a region relevant for social perception, behavior and reward. Here, we tested the hypothesis that the basolateral amygdala (BLA) plays a causal role in motivating behavioral responses to 50-kHz and 22-kHz USVs. Rats with lesions of the BLA or sham lesions were repeatedly exposed to playback of either 50-kHz or 22-kHz USVs in a radial maze. Compared to sham rats, BLA-lesioned rats spent less time in the arms close to the USV speaker during playback of both 50-kHz or 22-kHz USVs. This difference in behavior was not due to impaired motor or general auditory abilities, indicating that BLA lesions selectively reduced the responsiveness to stimuli with social significance. This finding provides further support for the hypothesis that the BLA plays an important role in motivating approach behavior to social reinforcers.
Assuntos
Percepção Auditiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Percepção Social , Vocalização Animal/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/patologia , Masculino , Ratos , Ratos Long-Evans , Ondas UltrassônicasRESUMO
We examined behaviors and neurotransmitter levels in the tgDimer mouse, a model for early Alzheimer's disease, that expresses exclusively soluble amyloid beta (Aß) dimers and is devoid of Aß plaques, astrogliosis, and neuroinflammation. Seven-month-old mice were subjected to tests of motor activity, attention, anxiety, habituation learning, working memory, and depression-related behaviors. They were impaired in nonselective attention and motor learning and showed anxiety- and despair-related behaviors. In 7- and 12-month-old mice, levels of acetylcholine, dopamine, and serotonin were measured in neostriatum, ventral striatum, prefrontal cortex, hippocampus, amygdala, and entorhinal cortex by high-performance liquid chromatography. The tgDimer mice had lower serotonin turnover rates in hippocampus, ventral striatum, and amygdala relative to wild type controls. The aged tgDimer mice had less hippocampal acetylcholine than adult tgDimers. Stress-test results, based on corticosterone levels, indicated an intact hypothalamus-pituitary-adrenal axis in 12-month-old mice. Since neither Aß plaques nor astrogliosis or neuroinflammation was responsible for these phenotypes, we conclude that Aß dimers contribute to neurotransmitter dysfunction and behavioral impairments, characteristic for the early stages of Alzheimer's disease.
Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Acetilcolina/metabolismo , Animais , Comportamento Animal , Química Encefálica , Modelos Animais de Doenças , Dopamina/metabolismo , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Camundongos Transgênicos , Serotonina/metabolismo , Estresse Psicológico/metabolismoRESUMO
Although the use of neuroimaging techniques has revealed much about the neural correlates of social decision making (SDM) in humans, it remains poorly understood how social stimuli are represented, and how social decisions are implemented at the neural level in humans and in other species. To address this issue, the establishment of novel animal paradigms allowing a broad spectrum of neurobiological causal manipulations and neurophysiological recordings provides an exciting tool to investigate the neural implementation of social valuation in the brain. Here, we discuss the potential of a rodent model, Rattus norvegicus, for the understanding of SDM and its neural underpinnings. Particularly, we consider recent data collected in a rodent prosocial choice task within a social reinforcement framework and discuss factors that could drive SDM in rodents.
Assuntos
Tonsila do Cerebelo/fisiologia , Comportamento de Escolha/fisiologia , Reforço Social , Recompensa , Animais , Humanos , RatosRESUMO
Nicotinic acetylcholine receptor (nAChR) subtypes containing the α4 subunit, particularly α4ß2 nAChRs, play an important role in cognitive functioning. The impact of the smoking cessation aid varenicline, a selective partial α4ß2 nAChR agonist, on (1) changes of central protein and mRNA expression of this receptor and (2) on memory deficits in a mouse model of cognitive impairment was investigated. Protein and mRNA expression of both the α4 and ß2 receptor subunits in mouse brain endothelial and hippocampal cells as well as hippocampus and neocortex tissues were determined by western blot and realtime PCR, respectively. The ß2 antibody showed low specificity, though. Tissues were examined following a 2-week oral treatment with various doses of varenicline (0.01, 0.1, 1, 3 mg/kg/day) or vehicle. In addition, episodic memory of mice was assessed following this treatment with an object recognition task using (1) normal mice and (2) animals with anticholinergic-induced memory impairment (i.p. injection of 0.5 mg/kg scopolamine). Varenicline dose-dependently increased protein expression of both the α4 and ß2 subunit in cell cultures and brain tissues, respectively, but had no effect on mRNA expression of both subunits. Scopolamine injection induced a significant reduction of object memory in vehicle-treated mice. By contrast, cognitive performance was not altered by scopolamine in varenicline-treated mice. In conclusion, a 2-week oral treatment with varenicline prevented memory impairment in the scopolamine mouse model. In parallel, protein, but not mRNA expression was upregulated, suggesting a posttranscriptional mechanism. Our findings suggest a beneficial effect of varenicline on cognitive dysfunction.
Assuntos
Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Nootrópicos/farmacologia , Receptores Nicotínicos/metabolismo , Vareniclina/farmacologia , Administração Oral , Animais , Encéfalo/metabolismo , Linhagem Celular , Cognição/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos Endogâmicos C57BL , RNA Mensageiro/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , EscopolaminaRESUMO
The Disrupted-in-Schizophrenia 1 (DISC1) protein plays a key role in behavioral control and vulnerability for mental illnesses, including schizophrenia. In this study we asked whether peripheral DISC1 protein levels in lymphocytes of patients diagnosed with schizophrenia can serve as a trait marker for the disease. Since a prominent comorbidity of schizophrenia patients is nicotine abuse or addiction, we also examined modulation of lymphocyte DISC1 protein levels in smokers, as well as the relationship between nicotine and DISC1 solubility status. We show decreased DISC1 levels in patients diagnosed with schizophrenia independent of smoking, indicating its potential use as a trait marker of this disease. In addition, lymphocytic DISC1 protein levels were decreased in smoking, mentally healthy individuals but not to the degree of overriding the trait level. Since DISC1 protein has been reported to exist in different solubility states in the brain, we also investigated DISC1 protein solubility in brains of rats treated with nicotine. Sub-chronic treatment with progressively increasing doses of nicotine from 0.25mg/kg to 1mg/kg for 15 days led to a decrease of insoluble DISC1 in the medial prefrontal cortex. Our results demonstrate that DISC1 protein levels in human lymphocytes are correlated with the diagnosis of schizophrenia independent of smoking and thus present a potential biomarker. Reduced DISC1 protein levels in lymphocytes of healthy individuals exposed to nicotine suggest that peripheral DISC1 could have potential for monitoring the effects of psychoactive substances.
Assuntos
Linfócitos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Esquizofrenia/sangue , Tabagismo/sangue , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Cotinina/sangue , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Linfócitos/efeitos dos fármacos , Masculino , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Ratos , Ratos Wistar , Análise de Regressão , Esquizofrenia/complicações , Tabagismo/complicaçõesRESUMO
Following our hypothesis that juvenile emotional and/or cognitive experience should affect learning performance at preweaning age as well as adulthood, the present study in female Wistar rats aimed to examine the impact of (i) avoidance training at preweaning age, (ii) exposure to repeated maternal separation, (iii) the combination of both, and (iv) the blockade of dopaminergic neurotransmission on adult two-way active avoidance learning in rats. We found that preweaning, i.e. three week old, rats were less capable of avoidance learning compared to adults. Our main findings revealed that preweaning avoidance training alone improved avoidance learning in adulthood. Furthermore, maternal separation alone also improved avoidance learning in preweaning and in adult rats, but this effect of maternal separation did not add up to the beneficial effect of preweaning avoidance training on adult learning. In addition, the pharmacological blockade of dopamine receptors during preweaning avoidance training via systemic application of haloperidol impaired preweaning avoidance performance in a dose-dependent manner. Testing the haloperidol-treated preweaning presumed "non-learners" as adults revealed that they still showed improved learning as adults. Taken together, our results strongly support the hypothesis that emotional as well as cognitive experience at preweaning age leaves an enduring "memory trace," which can facilitate learning in adulthood. Our pharmaco-behavioral studies suggest that unlike the adult brain, preweaning learning and memory formation is less dependent on dopaminergic mechanisms, which raises the intriguing question of possible alternative pathways.