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1.
Behav Neurosci ; 135(4): 540-549, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34165996

RESUMO

The present study examined the effects of the muscarinic acetylcholine receptor (mAChR) antagonist, scopolamine, on standard contextual fear conditioning (sCFC). It compared effects of the drug on acquisition (post-shock freezing) versus 24-hr retention of a context-shock association acquired after one or three pairings of a context with unsignaled shock. During single-trial sCFC, systemic scopolamine (0.5 mg/kg, i.p.) prior to training abolished both post-shock and retention freezing (Experiment 1). This same injection during multiple-trial sCFC also abolished post-shock freezing and impaired 24-hr retention freezing (Experiment 2). These results indicate that cholinergic signaling mediates both acquisition and 24-hr retention of a context-shock association across different trial parameters. Experiment 3 further explored these effects by infusing scopolamine (35 µg per side) into the dorsal hippocampus (dHPC) prior to training in single versus multiple-trial sCFC. This infusion spared post-shock but abolished retention test freezing in single-trial sCFC (Experiment 3A), and had no effect on multiple-trial sCFC (Experiment 3B). The current findings suggest that brain-wide cholinergic signaling mediates acquisition and retention of single-trial sCFC. Despite this, while muscarinic cholinergic signaling in the dHPC does mediate retention of single-trial sCFC, it is not required for acquisition of either variant, or retention of multiple-trial sCFC. These findings also rule out impaired sensory processing of contextual cues as a mechanism of impaired context learning by dHPC scopolamine. The results are discussed in relation to the role of cholinergic function across multiple brain memory systems in elemental versus configural forms of contextual fear conditioning (Fanselow, 2010; Rudy, 2009). (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Assuntos
Condicionamento Clássico , Medo , Animais , Reação de Congelamento Cataléptica , Hipocampo , Ratos , Ratos Long-Evans , Receptores Muscarínicos
2.
Stress ; 24(5): 602-611, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34030584

RESUMO

Chronic unpredictable mild stress (CUMS) is a widely used model to study stress-coping strategies in rodents. Different factors have been shown to influence whether animals adopt passive or active coping responses to CUMS. Individual adaptation and susceptibility to the environment seem to play a critical role in this process. To further investigate this relationship, we examined the effects of CUMS on Carioca high- and low-conditioned freezing rats (CHF and CLF, respectively), bidirectional lines of animals selected for high and low freezing in response to contextual cues that were previously associated with footshocks. For this purpose, the behavior of CHF and CLF animals was evaluated in the contextual fear conditioning, open field, elevated T maze, and forced swimming tests before and after 21 days of CUMS. For all tests, CHF rats were more susceptible to the effects of CUMS compared to CLF. CHF animals exposed to CUMS displayed a reduction in freezing behavior, decreased number of entries and time spent in the center of the open field, greater latencies to become immobile, and increased avoidance and escaping behaviors in the elevated T maze. Overall, these findings support the hypothesis that a heightened susceptibility to the environment exerts a strong influence on coping responses to chronic stress.


Assuntos
Medo , Estresse Psicológico , Adaptação Psicológica , Animais , Comportamento Animal , Depressão , Modelos Animais de Doenças , Reação de Congelamento Cataléptica , Ratos
3.
Neurosci Lett ; 751: 135777, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33647396

RESUMO

Previous research has implicated the ventral pole of the hippocampus in regulating anxiety. However, most rat studies examining the specific contribution of the ventral hippocampus have utilized techniques that have nonspecific effects and/or create nonreversible damage to the region. The present study sought to characterize the role of ventral hippocampal CaMKIIα-expressing neurons in modulating anxiety- and fear-like behavior during exposure to a variety of threatening stimuli. Five weeks prior to testing, adult male Long-Evans hooded rats received ventral hippocampal viral-vector infusions expressing either AAV8-CaMKIIα-hM4D-mCherry (DREADD) or AAV8-CaMKIIα-EGFP (GFP). DREADD transfection allowed for the specific, noninvasive and temporary inhibition of the ventral hippocampus (vHC) immediately before threat presentation. Rats were evaluated for behaviors congruent with anxiety- or fear-like defensive states during testing in the elevated plus-maze (EPM) and light-dark test (LDT), or post footshock freezing and footshock-induced contextual freezing, respectively. Analyses revealed a significant effect of vHC inhibition that was dependent on the type of threat exposure. Specifically, DREADD-induced silencing of vHC neurons reduced anxiety-like behavior in the EPM and LDT, without reliably affecting footshock-induced fear. These data add to a growing literature implicating the vHC as a key region involved in controlling the expression of anxiety in rodents, primates and humans.


Assuntos
Ansiedade/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Reação de Congelamento Cataléptica , Hipocampo/metabolismo , Animais , Ansiedade/fisiopatologia , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Proteínas de Ligação ao Cálcio/genética , Drogas Desenhadas/farmacologia , Medo , Hipocampo/citologia , Hipocampo/fisiologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Long-Evans
4.
Nat Commun ; 12(1): 1040, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33589613

RESUMO

Animals exhibit innate defense behaviors in response to approaching threats cued by the dynamics of sensory inputs of various modalities. The underlying neural circuits have been mostly studied in the visual system, but remain unclear for other modalities. Here, by utilizing sounds with increasing (vs. decreasing) loudness to mimic looming (vs. receding) objects, we find that looming sounds elicit stereotypical sequential defensive reactions: freezing followed by flight. Both behaviors require the activity of auditory cortex, in particular the sustained type of responses, but are differentially mediated by corticostriatal projections primarily innervating D2 neurons in the tail of the striatum and corticocollicular projections to the superior colliculus, respectively. The behavioral transition from freezing to flight can be attributed to the differential temporal dynamics of the striatal and collicular neurons in their responses to looming sound stimuli. Our results reveal an essential role of the striatum in the innate defense control.


Assuntos
Córtex Auditivo/fisiologia , Corpo Estriado/fisiologia , Reação de Fuga/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Instinto , Estimulação Acústica , Animais , Córtex Auditivo/anatomia & histologia , Percepção Auditiva/fisiologia , Corpo Estriado/anatomia & histologia , Sinais (Psicologia) , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/fisiologia , Som , Colículos Superiores/anatomia & histologia , Colículos Superiores/fisiologia
5.
Acta Neuropsychiatr ; 33(3): 148-155, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33593455

RESUMO

OBJECTIVE: Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation, and expression of conditioned fear. METHODS: Male Sprague-Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily × 3), (i) throughout the period from (and including) acquisition to (and including) expression, (ii) during acquisition but not expression, (iii) after acquisition only, and (iv) during expression only. RESULTS: The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, that is during memory consolidation, did not impact the expression of conditioned fear. CONCLUSION: Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.


Assuntos
Medo/efeitos dos fármacos , Fenclonina/farmacologia , Antagonistas da Serotonina/farmacologia , Serotonina/metabolismo , Animais , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico , Modelos Animais de Doenças , Medo/psicologia , Fenclonina/administração & dosagem , Reação de Congelamento Cataléptica/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Serotonina/deficiência , Antagonistas da Serotonina/administração & dosagem
6.
J Therm Biol ; 95: 102819, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33454047

RESUMO

2,3,5-trimethyl-3-thiazoline (TMT) is a chemical compound that is extracted from red fox urine and can be used to artificially simulate the presence of a predator. The purpose of this study was to test the hypothesis that TMT would block entry into torpor in the calorically restricted C57Bl/6 mouse. We first demonstrated that TMT induced fear in the mouse. Exposure to TMT induced an acute freeze response (67.2 ± 6.7% of time), as compared to 6.7 ± 1.7% when exposed to water. Further, exposure to TMT for 30 min led to elevated circulating corticosterone levels, 377 ± 33 ng/ml, as compared to 29 ± 4 ng/ml when exposed to water. When mice were exposed to TMT during the dark or light phase, body temperature (Tb) dropped by 1.7 ± 0.9 °C and 0.7 ± 1.1 °C, respectively, over the first 110 min after exposure. To determine whether TMT influences daily torpor, mice were calorically restricted and exposed to either water or TMT. Mice were exposed 30 min before the start of torpor, determined by the bout of the previous day. Exposure to TMT significantly (p < 0.01) blunted the fall in the minimum Tb from 28.8 ± 0.3 °C (water) to 30.1 ± 0.6 °C (TMT) and significantly (p < 0.05) decreased the amount of time Tb was under 32 °C, from 431 ± 48 min (water) to 292 ± 78 min (TMT). These results establish that mice perceived the scent of TMT as a physiologically stressful stimulus and that Tb response is modestly blunted in the presence of that stressor. Our experiment highlights the intricate interplay between predation risk and energy conservation.


Assuntos
Restrição Calórica , Reação de Congelamento Cataléptica , Odorantes , Estresse Psicológico/fisiopatologia , Torpor , Animais , Corticosterona/sangue , Medo , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fotoperíodo , Estresse Fisiológico , Estresse Psicológico/etiologia , Tiazóis/toxicidade
7.
J Vis Exp ; (167)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33491674

RESUMO

Fear- and anxiety-related behaviors significantly contribute to an organism's survival. However, exaggerated defensive responses to perceived threat are characteristic of various anxiety disorders, which are the most prevalent form of mental illness in the United States. Discovering the neurobiological mechanisms responsible for defensive behaviors will aid in the development of novel therapeutic interventions. Pavlovian fear conditioning is a widely used laboratory paradigm to study fear-related learning and memory. A major limitation of traditional Pavlovian fear conditioning paradigms is that freezing is the only defensive behavior monitored. We recently developed a modified Pavlovian fear conditioning paradigm that allows us to study both conditioned freezing and flight (also known as escape) behavior within individual subjects. This model employs higher intensity footshocks and a greater number of pairings between the conditioned stimulus and unconditioned stimulus. Additionally, this conditioned flight paradigm utilizes serial presentation of pure tone and white noise auditory stimuli as the conditioned stimulus. Following conditioning in this paradigm, mice exhibit freezing behavior in response to the tone stimulus, and flight responses during the white noise. This conditioning model can be applied to the study of rapid and flexible transitions between behavioral responses necessary for survival.


Assuntos
Comportamento Animal , Condicionamento Clássico/fisiologia , Reação de Fuga/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Animais , Extinção Psicológica , Feminino , Congelamento , Masculino , Memória/fisiologia , Camundongos Endogâmicos C57BL , Gravação em Vídeo
8.
Sci Rep ; 10(1): 20529, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239732

RESUMO

Deep brain stimulation (DBS) in the bed nucleus of the stria terminalis (BST), a region implicated in the expression of anxiety, shows promise in psychiatric patients, but its effects throughout the limbic system are largely unknown. In male Wistar rats, we first evaluated the neural signature of contextual fear (N = 16) and next, of the anxiolytic effects of high-frequency electrical stimulation in the BST (N = 31), by means of c-Fos protein expression. In non-operated animals, we found that the left medial anterior BST displayed increased c-Fos expression in anxious (i.e., context-conditioned) versus control subjects. Moreover, control rats showed asymmetric expression in the basolateral amygdala (BLA) (i.e., higher intensities in the right hemisphere), which was absent in anxious animals. The predominant finding in rats receiving bilateral BST stimulation was a striking increase in c-Fos expression throughout much of the left hemisphere, which was not confined to the predefined regions of interest. To conclude, we found evidence for lateralized c-Fos expression during the expression of contextual fear and anxiolytic high-frequency electrical stimulation of the BST, particularly in the medial anterior BST and BLA. In addition, we observed an extensive and unexpected left-sided c-Fos spread following bilateral stimulation in the BST.


Assuntos
Estimulação Encefálica Profunda , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleos Septais/metabolismo , Aclimatação , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal , Condicionamento Clássico , Eletrodos , Reação de Congelamento Cataléptica , Masculino , Neurônios/metabolismo , Ratos Wistar
9.
Behav Res Ther ; 135: 103763, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33160269

RESUMO

Infants tend to forget experiences much more rapidly than older individuals, a phenomenon referred to as infantile amnesia. This robust, cross-species phenomenon is commonly used to examine memory development. However, in this set of experiments, we examined the novel hypothesis that the expression of infantile amnesia is related to resilience/vulnerability. We conditioned infant rats to associate a white noise with shock. Animals were tested for memory of the association ~1 week later. We found that infants that expressed better memory of the aversive association emitted more vocalizations (indicative of higher levels of distress) when separated from their mother earlier in infancy (Experiment 1). Better expression of memory in infancy also predicted higher levels of conditioned fear (Experiment 2) and anxiety-like behavior (in a light-dark box; Experiment 3) in adulthood. Furthermore, probiotic-treatment administered early in development reduced anxiety-like behavior in animals that exhibited good expression of memory for an aversive association learnt in infancy (Experiment 4). However, the same treatment was ineffective if administered in adulthood. Taken together, these results suggest that individual differences in infants' memory for an aversive association predict anxiety-like behavior throughout development, and that early administration of probiotics can reduce anxiety-like behavior in "at-risk" animals.


Assuntos
Ansiedade/psicologia , Comportamento Animal , Condicionamento Clássico , Medo , Reação de Congelamento Cataléptica , Memória , Animais , Probióticos , Ratos , Vocalização Animal
10.
Learn Mem ; 27(12): 483-487, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33199472

RESUMO

The efficacy of pharmacological disruption of fear memory reconsolidation depends on several factors, including memory strength and age. We built on previous observations that systemic treatment with the nootropic nefiracetam potentiates cued fear memory destabilization to facilitate mifepristone-induced reconsolidation impairment. Here, we applied nefiratecam and mifepristone to strongly conditioned, 1-wk-old contextual fear memories in male rats. Unexpectedly, the combined treatment did not result in impairment of contextual fear expression. However, mifepristone did reduce freezing to a novel context. These observations suggest that strong and established contextual fear memories do undergo destabilization without the need for pharmacological facilitation, and that impairments in strong context fear memory reconsolidation can manifest as a reduction in generalization.


Assuntos
Medo/efeitos dos fármacos , Generalização Psicológica/efeitos dos fármacos , Memória/efeitos dos fármacos , Mifepristona/toxicidade , Nootrópicos/toxicidade , Animais , Condicionamento Psicológico/efeitos dos fármacos , Extinção Psicológica , Reação de Congelamento Cataléptica , Masculino , Pirrolidinonas/farmacologia , Ratos
11.
Mol Brain ; 13(1): 134, 2020 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-33028360

RESUMO

Most individuals undergo traumatic stresses at some points in their life, but only a small proportion develop stress-related disorders such as anxiety diseases and posttraumatic stress disorder (PTSD). Although stress susceptibility is one determinant of mental disorders, the underlying mechanisms and functional implication remain unclear yet. We found that an increased amount of freezing that animals exhibited in the intertrial interval (ITI) of a stress-enhanced fear learning paradigm, predicts ensuing PTSD-like symptoms whereas resilient mice show ITI freezing comparable to that of unstressed mice. To examine the behavioral features, we developed a systematic analytical approach for ITI freezing and stress susceptibility. Thus, we provide a behavioral parameter for prognosis to stress susceptibility of individuals in the development of PTSD-like symptoms as well as a new mathematical means to scrutinize freezing behavior.


Assuntos
Medo/fisiologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Doença Aguda , Animais , Ansiedade/fisiopatologia , Comportamento Animal/fisiologia , Suscetibilidade a Doenças , Extinção Psicológica , Reação de Congelamento Cataléptica/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Fenótipo , Reprodutibilidade dos Testes
12.
Behav Neurosci ; 134(5): 460-470, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33001682

RESUMO

The current study further examined the effect of the muscarinic acetylcholine antagonist, scopolamine, on the Context Preexposure Facilitation Effect (CPFE; Robinson-Drummer, Dokovna, Heroux, & Stanton, 2016). In the CPFE, context representations formed during the preexposure phase are retrieved and associated with immediate shock during the training phase and expressed as freezing during a 24-hr retention phase. Scopolamine abolished postshock and retention freezing when administered systemically prior to preexposure (Experiment 1A) or immediate-shock training (Experiment 1B). Pretraining infusion of scopolamine into dorsal hippocampus (dHPC) disrupted both postshock and retention freezing (Experiments 2A) and retention freezing when the postshock freezing test was omitted (Experiment 2B) but did not alter expression of freezing behavior to an auditory fear stimulus (Experiment 2C). Finally, pretraining scopolamine infusion into ventral hippocampus (vHPC) also abolished postshock and retention test freezing (Experiment 3). These findings suggest similar roles for muscarinic receptor activity in both the dHPC and vHPC in the CPFE. This study advances understanding of the neurobiology of the CPFE by showing that context-shock associations are not learned following disruption of the cholinergic and/or hippocampal function on either the preexposure or training day. Existing theories of the CPFE (Rudy, 2009) have inferred this effect based on impaired 24-hr retention observed in previous studies (Matus-Amat, Higgins, Barrientos, & Rudy, 2004; Robinson-Drummer et al., 2016). However, the present study is the first to demonstrate it directly by including a postshock freezing measure. Further, this study is the first to identify vHPC as another important region necessary for context-shock learning during the CPFE paradigm. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


Assuntos
Condicionamento Clássico , Medo , Reação de Congelamento Cataléptica , Hipocampo/metabolismo , Receptores Muscarínicos/metabolismo , Animais , Feminino , Masculino , Ratos , Ratos Long-Evans
13.
Pharmacol Biochem Behav ; 197: 173019, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32827503

RESUMO

Evidence from clinical and epidemiological studies point towards an association between generalized anxiety disorder (GAD) and alcohol abuse. In the present study we investigated whether a similar relationship could be observed in an animal model of GAD. Specifically, we evaluated the alcohol intake of Carioca High- and Low-conditioned Freezing rats (CHF and CLF, respectively). Sex differences in alcohol drinking behavior were also studied. Male and female rats from randomized crossbreeding populations served as controls (CTL). Free- and forced-choice protocols were used to measure alcohol consumption, and quinine and saccharin were used as taste control solutions. Our results indicate that CHF rats consumed more alcohol than CLF and CTL ones in both the free-choice (6 and 10% concentrations) and the forced-choice (10% concentration) conditions. CHF female rats exhibited the highest amount of alcohol intake in the forced-choice condition. CHF females also consumed more quinine than CHF male rats. Finally, CHF rats exhibited lower saccharin consumption compared to CLF and CTL animals. Altogether, these results support the hypothesis that there is a positive relationship between anxiety and alcohol intake, and provide further evidence for the use of CHF rats as a model of GAD.


Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo/complicações , Transtornos de Ansiedade/complicações , Condicionamento Psicológico/efeitos dos fármacos , Modelos Animais de Doenças , Reação de Congelamento Cataléptica/efeitos dos fármacos , Animais , Etanol , Medo , Feminino , Masculino , Fenótipo , Quinina , Ratos , Ratos Wistar , Sacarina , Percepção Gustatória
14.
Synapse ; 74(12): e22180, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32644234

RESUMO

Pharmacological magnetic resonance imaging (phMRI) allows the visualization of brain pharmacological effects of drugs using functional MRI (fMRI). phMRI can help us facilitate central nervous system (CNS) drug development. However, there have been few studies demonstrating the dose relationship of the fMRI response induced by CNS drugs to underlying target engagement or behavioral efficacy. To clarify these relationships, we examined receptor occupancy measurements using positron emission tomography (PET) (n = 3~5), fMRI (n = 5~8) and a cataleptic behavior (n = 6) with raclopride, a dopamine D2 receptor antagonist (8, 20, and 200 µg/kg) on Wistar rats. Dopamine D2 receptor occupancy was increased dose dependently by raclopride (41.8 ± 2.7%, 8 µg/kg; 64.9 ± 2.8%, 20 µg/kg; 83.1 ± 3.0%, 200 µg/kg). phMRI study revealed significant positive responses to raclopride at 200 µg/kg specifically in the striatum and nucleus accumbens, related to dopaminergic system. Slight fMRI responses were observed at 20 µg/kg in some areas corresponding to the striatum and nucleus accumbens. There were no noticeable fMRI responses at 8 µg/kg raclopride administration. Raclopride at 200 µg/kg significantly increased the cataleptic score, although, at 8 and 20 µg/kg, raclopride had no significant effects. These findings showed that raclopride-induced fMRI responses were observed at doses inducing cataleptic behavior and high D2 receptor occupancy, suggesting that phMRI can be useful for dose selection in clinical trial as an evaluation method of brain activity, which reflects behavioral responses induced by target engagements.


Assuntos
Corpo Estriado/metabolismo , Antagonistas de Dopamina/farmacocinética , Reação de Congelamento Cataléptica/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Racloprida/farmacocinética , Animais , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/fisiologia , Imageamento por Ressonância Magnética , Masculino , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/fisiologia , Tomografia por Emissão de Pósitrons , Ligação Proteica , Ratos , Ratos Wistar , Receptores de Dopamina D2/metabolismo
15.
Brain Struct Funct ; 225(7): 2029-2044, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32642914

RESUMO

Increasing evidence points to the engagement of the lateral habenula (LHb) in the selection of appropriate behavioral responses in aversive situations. However, very few data have been gathered with respect to its role in fear memory formation, especially in learning paradigms in which brain areas involved in cognitive processes like the hippocampus (HPC) and the medial prefrontal cortex (mPFC) are required. A paradigm of this sort is trace fear conditioning, in which an aversive event is preceded by a discrete stimulus, generally a tone, but without the close temporal contiguity allowing for their association based on amygdala-dependent information processing. In a first experiment, we analyzed cellular activations (c-Fos expression) induced by trace fear conditioning in subregions of the habenular complex, HPC, mPFC and amygdala using a factorial analysis to unravel functional networks through correlational analysis of data. This analysis suggested that distinct LHb subregions engaged in different aspects of conditioning, e.g. associative processes and onset of fear responses. In a second experiment, we performed chemogenetic LHb inactivation during the conditioning phase of the trace fear conditioning paradigm and subsequently assessed contextual and tone fear memories. Whereas LHb inactivation did not modify rat's behavior during conditioning, it induced contextual memory deficits and enhanced fear to the tone. These results demonstrate the involvement of the LHb in fear memory. They further suggest that the LHb is engaged in learning about threatening environments through the selection of relevant information predictive of a danger.


Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Habenula/metabolismo , Memória/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Reação de Congelamento Cataléptica/fisiologia , Masculino , Atividade Motora/fisiologia , Córtex Pré-Frontal/metabolismo , Ratos Long-Evans
16.
Brain Struct Funct ; 225(7): 1957-1966, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32594260

RESUMO

Electrical stimulation of the dorsolateral periaqueductal gray (dlPAG) in rats has been shown to elicit panic-like behaviour and can be a useful as an unconditioned stimulus for modelling anticipatory fear and agoraphobia in a contextual fear conditioning paradigm. In this study, we further analysed our previous data on the effects of escitalopram (a selective serotonin reuptake inhibitor, SSRI) and buspirone (a 5-HT1A receptor partial agonist) on dlPAG-induced anticipatory fear behaviour in a rat model using freezing as a measure. We then attempted to unravel some of the interactions with dopamine signalling using tyrosine hydroxylase (TH) immunohistochemistry to probe the effects on dopaminergic neurons. We showed that acute treatment of escitalopram, but not buspirone, was effective in reducing anticipatory freezing behaviour, while chronic administrations of both drugs were effective. We found that the dlPAG stimulation induced increase number of dopaminergic neurons in the ventral tegmental area (VTA) which was reversed in both chronic buspirone and escitalopram groups. We further found a strong positive correlation between the number of dopaminergic neurons and freezing in the VTA and showed positive correlations between dopaminergic neurons in the VTA and substantia nigra pars compacta (SNpc) in escitalopram and buspirone groups, respectively. Overall, we showed that chronic treatment with an SSRI and a 5-HT1A agonist reduced anticipatory freezing behaviour which seems to be associated, through correlative studies, with a reversal of dlPAG stimulation induced increase in number of dopaminergic neurons in the VTA and/or SNpc.


Assuntos
Buspirona/farmacologia , Citalopram/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Mesencéfalo/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Estimulação Encefálica Profunda , Neurônios Dopaminérgicos/metabolismo , Estimulação Elétrica , Medo/efeitos dos fármacos , Medo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Masculino , Mesencéfalo/metabolismo , Ratos , Ratos Wistar
17.
J Ethnopharmacol ; 260: 113048, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32525067

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lavender (Lavandula angustifolia) essential oil (EO) has a long history of use in emotional illness, including anxiety disorders. Cognitive mechanisms of learning and memory play a pivotal role in the etiology and maintenance of anxiety since exposure to cues related to aversive situations induces high arousal and anticipatory anxiety. Memory become labile after its reactivation and can be modulated by reconsolidation or extinction. Inhibition of memory reconsolidation or facilitation of memory extinction may be effective in preventing or minimizing the effect of contextual cues on anticipatory anxiety. AIM OF THE STUDY: We investigated the effect of Lavandula angustifolia EO in the memory updating of conditioned contextual fear. MATERIALS AND METHODS: Adult male C57Bl6 mice were submitted to fear conditioning. Two days after conditioning the mice underwent a reactivation session in a hybrid context and were then immediately exposed to vaporized water or essential oil at concentrations of 1%, 2.5% or 5% for 3 h. Two days later, the mice were tested in the original or an altered context and their freezing behavior was measured. In addition, mice were subjected to a fear memory recovery protocol followed by a reinstatement session. RESULTS: In the contextual fear test, 1% essential oil, but not 2.5% or 5%, reduced the freezing behavior response, whereas after a reinstatement session, exposure to 1% essential oil increased the freezing behavior response. CONCLUSIONS: These results suggest that Lavandula angustifolia essential oil enhances memory extinction and, consequently, inhibits memory updating.


Assuntos
Aromaterapia , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Memória/efeitos dos fármacos , Óleos Voláteis/administração & dosagem , Óleos Vegetais/administração & dosagem , Administração por Inalação , Animais , Sinais (Psicologia) , Reação de Congelamento Cataléptica/efeitos dos fármacos , Humanos , Lavandula , Camundongos Endogâmicos C57BL , Fatores de Tempo
18.
Horm Behav ; 124: 104777, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439347

RESUMO

Neuropeptide oxytocin (OT) is involved in the regulation of social and non-social behaviour. The central nucleus of amygdala (CeA), part of the limbic system, plays an important role in learning, memory, anxiety and reinforcing mechanisms. CeA has been shown to be rich in OT receptors in rodents. Our previous findings indicated that OT in the rat CeA has a dose dependent rewarding and anxiolytic effect. The aim of our present study was to examine in the CeA the possible interaction of OT and D2 dopamine (DA) receptor antagonist Sulpiride on reinforcement in place preference test and on anxiety in elevated plus maze test. Wistar rats were microinjected bilaterally with 10 ng OT. In different group of animals 4 µg D2 DA receptor antagonist was applied. Other animals received D2 DA receptor antagonist 15 min before 10 ng OT treatment or vehicle solution into the CeA. Rats receiving 10 ng OT spent significantly longer time in the treatment quadrant during the test session in conditioned place preference test. Prior treatment with D2 DA receptor antagonist blocked the rewarding effects of OT. Antagonist in itself did not influence the time rats spent in the treatment quadrant. In elevated plus maze test, rats receiving 10 ng OT spent significantly longer time on the open arms. Prior treatment with D2 DA receptor antagonist blocked the effects of OT. Our results show that DA system plays a role in positive reinforcing and anxiolytic effects of OT because D2 DA receptor antagonist can block these actions.


Assuntos
Ansiolíticos/farmacologia , Ocitocina/farmacologia , Receptores de Dopamina D2/fisiologia , Comportamento Espacial/efeitos dos fármacos , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2/farmacologia , Medo/efeitos dos fármacos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Ocitocina/metabolismo , Receptores de Ocitocina/fisiologia , Reforço Psicológico , Recompensa , Sulpirida/farmacologia
19.
Pharmacol Biochem Behav ; 194: 172938, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32376258

RESUMO

Evidence indicates that periaqueductal gray matter (PAG) plays an important role in defensive responses and pain control. The activation of cannabinoid type-1 (CB1) or mu-opioid (MOR) receptors in the dorsal region of this structure (dPAG) inhibits fear and facilitates antinociception induced by different aversive stimuli. However, it is still unknown whether these two receptors work cooperatively in order to achieve these inhibitory actions. This study investigated the involvement and a likely interplay between CB1 and MOR receptors localized into the dPAG on the regulation of fear-like defensive responses and antinociception (evaluated in tail-flick test) evoked by dPAG chemical stimulation with N-methyl-d-aspartate (NMDA). Before the administration of NMDA, animals were first intra-dPAG injected with the CB1 agonist ACEA (0.5 pmol), or with the MOR agonist DAMGO (0.5 pmol) in combination with the respective antagonists AM251 (CB1 antagonist, 100 pmol) or CTOP (MOR antagonist, 1 nmol). To investigate the interplay between these receptors, microinjection of CTOP was combined with ACEA, or microinjection of AM251 was combined with DAMGO. Our results showed that both the intra-PAG treatments with ACEA or DAMGO inhibited NMDA-induced freezing expression, whereas only the treatment with DAMGO increased antinociception induced with NMDA, which are completely blocked by its respective antagonists. Interestingly, the inhibitory effects of ACEA or DAMGO on freezing was blocked by CTOP and AM251, respectively, indicating a functional interaction between these two receptors in the mediation of defensive behaviors. However, this cooperative interaction was not observed during the NMDA-induced antinociception. Our findings indicate that there is a cooperative action between the MOR and CB1 receptors within the dPAG and it is involved in the mediation of NMDA-induced defensive responses. Additionally, the MORs into the dPAG are involved in the modulation of the antinociceptive effects that follow a fear-like defense-reaction induced by dPAG chemical stimulation with NMDA.


Assuntos
Medo/efeitos dos fármacos , N-Metilaspartato/farmacologia , Nociceptividade/efeitos dos fármacos , Substância Cinzenta Periaquedutal/metabolismo , Receptor CB1 de Canabinoide/metabolismo , Receptores Opioides mu/metabolismo , Analgésicos Opioides/farmacologia , Animais , Ácidos Araquidônicos/farmacologia , Comportamento Animal/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Agonistas de Aminoácidos Excitatórios/farmacologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Masculino , Microinjeções , Dor/tratamento farmacológico , Dor/metabolismo , Medição da Dor/efeitos dos fármacos , Piperidinas/farmacologia , Pirazóis/farmacologia , Ratos , Receptores Opioides mu/agonistas , Receptores Opioides mu/antagonistas & inibidores , Somatostatina/análogos & derivados , Somatostatina/farmacologia
20.
Elife ; 92020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32207681

RESUMO

Innate defensive behaviors, such as freezing, are adaptive for avoiding predation. Freezing-related midbrain regions project to the cerebellum, which is known to regulate rapid sensorimotor integration, raising the question of cerebellar contributions to freezing. Here, we find that neurons of the mouse medial (fastigial) cerebellar nuclei (mCbN), which fire spontaneously with wide dynamic ranges, send glutamatergic projections to the ventrolateral periaqueductal gray (vlPAG), which contains diverse cell types. In freely moving mice, optogenetically stimulating glutamatergic vlPAG neurons that express Chx10 reliably induces freezing. In vlPAG slices, mCbN terminals excite ~20% of neurons positive for Chx10 or GAD2 and ~70% of dopaminergic TH-positive neurons. Stimulating either mCbN afferents or TH neurons augments IPSCs and suppresses EPSCs in Chx10 neurons by activating postsynaptic D2 receptors. The results suggest that mCbN activity regulates dopaminergic modulation of the vlPAG, favoring inhibition of Chx10 neurons. Suppression of cerebellar output may therefore facilitate freezing.


Assuntos
Cerebelo/fisiologia , Neurônios/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Sinapses/fisiologia , Animais , Comportamento Animal , Feminino , Reação de Congelamento Cataléptica , Proteínas de Homeodomínio/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Optogenética , Receptores Dopaminérgicos/fisiologia , Reflexo de Sobressalto , Potenciais Sinápticos , Fatores de Transcrição/fisiologia
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