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1.
Neurobiol Learn Mem ; 167: 107116, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31740383

RESUMO

Recent work indicates that the bed nucleus of the stria terminalis (BNST) is critically involved in the regulation of conditioned fear responses to unpredictable threats. Here we examined whether the involvement of the BNST in contextual fear conditioning in male rats depends on the imminence of shock after placement in the conditioning chamber. Specifically, we hypothesized that the BNST supports contextual freezing after conditioning with delayed, but not imminent, footshock (relative to placement in the context). Rats were implanted with cannulae targeting the BNST and underwent a contextual fear conditioning procedure in which a single footshock unconditioned stimulus (US) was delivered either 1 min or 9 min after the rat was placed in the context; the rats received a total of four identical conditioning sessions over two days, all with equivalent exposure to the context. Contexts associated with either imminent or delayed US onsets produced distinct patterns of freezing and shock-induced activity but freezing in each case was context-dependent. Reversible inactivation of the BNST reduced the expression of contextual freezing in the context paired with delayed (9 min), but not imminent (1 min), footshock onset. Implications of these data are discussed in the light of recent conceptualizations of BNST function, as well as for anxiety behaviors.


Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Núcleos Septais/fisiologia , Animais , Comportamento Animal/fisiologia , Eletrochoque , Masculino , Ratos Long-Evans
2.
Horm Behav ; 89: 137-144, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28104355

RESUMO

Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST). To further explore the nature of this effect, we infused ALLO into the BNST of male rats prior to both conditioning and testing. We found that suppression of contextual fear occurred when the hormone was present during either conditioning or testing but not during both procedures, suggesting that ALLO acts in a state-dependent manner within the BNST. A shift in interoceptive context during testing for animals conditioned under ALLO provided further support for this mechanism of hormonal action on contextual fear. Interestingly, infusions of ALLO into the basolateral amygdala produced a state-independent suppression of both conditioned contextual and auditory freezing. Altogether, these results suggest that ALLO can influence the acquisition and expression of fear memories by both state-dependent and state-independent mechanisms.


Assuntos
Medo/efeitos dos fármacos , Pregnanolona/farmacologia , Núcleos Septais/efeitos dos fármacos , Estimulação Acústica , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/psicologia , Aprendizagem por Associação/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Masculino , Ratos , Transtornos de Estresse Pós-Traumáticos
3.
Psychoneuroendocrinology ; 141: 105776, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35489312

RESUMO

The increased susceptibility of women to stress and trauma-related disorders compared to men suggests a role for ovarian hormones in modulating fear and anxiety. In both humans and rodents, estrogen and progesterone have been shown to influence fear learning during acquisition, expression, and extinction. Recently, we showed that allopregnanolone (ALLO), a progesterone (PROG) metabolite and GABAA receptor potentiator, confers state-dependent contextual fear when infused into the bed nucleus of the stria terminalis of male rats. In order to determine whether estrous cycle-related fluctuations in circulating PROG confer state-dependent contextual fear in female rats, animals received Pavlovian fear conditioning during an estrous cycle phase when PROG was either low (late diestrus) or high (late proestrus). After conditioning, animals were tested for contextual fear in either the same or different estrous cycle phase. Subjects conditioned in diestrus and tested in proestrus showed lower levels of contextual fear compared to subjects conditioned and tested in the same estrous cycle phase (either diestrus or proestrus), suggesting a state-dependent effect of estrous cycle phase on fear learning. This state dependence was asymmetric, however, as animals trained in proestrus and tested in diestrus exhibited high levels of contextual fear. In ovariectomized (OVX) females treated acutely with either PROG or vehicle, state dependence was not observed. These results suggest that the hormonal state in diestrus may play a role in conferring state dependence to conditioned fear in naturally cycling female rats but not in an OVX model.


Assuntos
Medo , Progesterona , Animais , Condicionamento Clássico , Estrogênios/farmacologia , Ciclo Estral , Feminino , Humanos , Masculino , Progesterona/metabolismo , Ratos
4.
Elife ; 82019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30946011

RESUMO

The bed nucleus of the stria terminalis (BNST) has been implicated in conditioned fear and anxiety, but the specific factors that engage the BNST in defensive behaviors are unclear. Here we examined whether the BNST mediates freezing to conditioned stimuli (CSs) that poorly predict the onset of aversive unconditioned stimuli (USs) in rats. Reversible inactivation of the BNST selectively reduced freezing to CSs that poorly signaled US onset (e.g., a backward CS that followed the US), but did not eliminate freezing to forward CSs even when they predicted USs of variable intensity. Additionally, backward (but not forward) CSs selectively increased Fos in the ventral BNST and in BNST-projecting neurons in the infralimbic region of the medial prefrontal cortex (mPFC), but not in the hippocampus or amygdala. These data reveal that BNST circuits regulate fear to unpredictable threats, which may be critical to the etiology and expression of anxiety.


Assuntos
Reação de Fuga , Medo , Rede Nervosa/fisiologia , Córtex Pré-Frontal/fisiologia , Núcleos Septais/fisiologia , Animais , Ansiedade , Ratos
5.
Transl Behav Med ; 8(1): 137-143, 2018 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-29385587

RESUMO

This commentary highlights the essential role of the social and behavioral sciences for genomic translation, and discusses some priority research areas in this regard. The first area encompasses genetics of behavioral, social, and neurocognitive factors, and how integration of these relationships might impact the development of treatments and interventions. The second area includes the contributions that social and behavioral sciences make toward the informed translation of genomic developments. Further, there is a need for behavioral and social sciences to inform biomedical research for effective implementation. The third area speaks to the need for increased outreach and education efforts to improve the public's genomic literacy such that individuals and communities can make informed health-related and societal (e.g., in legal or consumer settings) decisions. Finally, there is a need to prioritize representation of diverse communities in genomics research and equity of access to genomic technologies. Examples from National Institutes of Health-based intramural and extramural research programs and initiatives are used to discuss these points.


Assuntos
Ciências do Comportamento , Genômica , Ciências Sociais , Pesquisa Translacional Biomédica , Ciências do Comportamento/métodos , Genômica/métodos , Humanos , Ciências Sociais/métodos , Pesquisa Translacional Biomédica/métodos
6.
J Forensic Sci ; 63(6): 1704-1711, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29464689

RESUMO

Insect stains produced by necrophagous flies are indistinguishable morphologically from human bloodstains. At present, no diagnostic tests exist to overcome this deficiency. As the first step toward developing a chemical test to recognize fly artifacts, polyclonal antisera were generated in rats against three distinct antigenic sequences of fly cathepsin D-like proteinase, an enzyme that is structurally distinct in cyclorrhaphous Diptera from other animals. The resulting rat antisera bound to artifacts produced by Protophormia terraenovae and synthetic peptides used to generate the polyclonal antisera, but not with any type of mammalian blood tested in immunoassays. Among the three antisera, anti-md3 serum displayed the highest reactivity for fly stains, demonstrated cross-reactivity for all synthetic peptides representing antigenic sequences of the mature fly enzyme, and bound artifacts originating from the fly digestive tract. Further work is needed to determine whether the antisera are suitable for non-laboratory conditions.


Assuntos
Artefatos , Catepsina D/imunologia , Dípteros , Soros Imunes/farmacologia , Immunoblotting , Animais , Manchas de Sangue , Comportamento Alimentar , Ciências Forenses , Conteúdo Gastrointestinal , Humanos , Mudanças Depois da Morte
7.
Nat Neurosci ; 21(3): 384-392, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29403033

RESUMO

The medial prefrontal cortex (mPFC) has been implicated in the extinction of emotional memories, including conditioned fear. We found that ventral hippocampal (vHPC) projections to the infralimbic (IL) cortex recruited parvalbumin-expressing interneurons to counter the expression of extinguished fear and promote fear relapse. Whole-cell recordings ex vivo revealed that optogenetic activation of vHPC input to amygdala-projecting pyramidal neurons in the IL was dominated by feed-forward inhibition. Selectively silencing parvalbumin-expressing, but not somatostatin-expressing, interneurons in the IL eliminated vHPC-mediated inhibition. In behaving rats, pharmacogenetic activation of vHPC→IL projections impaired extinction recall, whereas silencing IL projectors diminished fear renewal. Intra-IL infusion of GABA receptor agonists or antagonists, respectively, reproduced these effects. Together, our findings describe a previously unknown circuit mechanism for the contextual control of fear, and indicate that vHPC-mediated inhibition of IL is an essential neural substrate for fear relapse.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Interneurônios/fisiologia , Masculino , Parvalbuminas/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Receptores de GABA/fisiologia , Somatostatina/metabolismo
8.
Nat Neurosci ; 21(9): 1291, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29988070

RESUMO

In the version of this article initially published, the traces in Fig. 1j and in Fig. 1k, right, were duplicated from the corresponding traces in Fig. 1c, bottom, and Fig. 1d, bottom right. The error has been corrected in the HTML and PDF versions of the article.

9.
Neuropsychopharmacology ; 42(13): 2537-2544, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28462941

RESUMO

Early psychological interventions, such as exposure therapy, rely on extinction learning to reduce the development of stress- and trauma-related disorders. However, recent research suggests that extinction often fails to reduce fear when administered soon after trauma. This immediate extinction deficit (IED) may be due to stress-induced dysregulation of neural circuits involved in extinction learning. We have shown that systemic ß-adrenoceptor blockade with propranolol rescues the IED, but impairs delayed extinction. Here we sought to determine the neural locus of these effects. Rats underwent auditory fear conditioning and then received either immediate (30 min) or delayed (24 h) extinction training. We used bilateral intracranial infusions of propranolol into either the infralimbic division of the medial prefrontal cortex (mPFC) or the basolateral amygdala (BLA) to examine the effects of ß-adrenoceptor blockade on immediate and delayed extinction learning. Interestingly, intra-BLA, but not intra-mPFC, propranolol rescued the IED; animals receiving intra-BLA propranolol prior to immediate extinction showed less spontaneous recovery of fear during extinction retrieval. Importantly, this was not due to impaired consolidation of the conditioning memory. In contrast, neither intra-BLA nor intra-mPFC propranolol affected delayed extinction learning. Overall, these data contribute to a growing literature suggesting dissociable roles for key nodes in the fear extinction circuit depending on the timing of extinction relative to conditioning. These data also suggest that heightened noradrenergic activity in the BLA underlies stress-induced extinction deficits. Propranolol may be a useful adjunct to behavioral therapeutic interventions in recently traumatized individuals who are at risk for developing trauma-related disorders.


Assuntos
Complexo Nuclear Basolateral da Amígdala/metabolismo , Extinção Psicológica/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores Adrenérgicos beta/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Animais , Percepção Auditiva/efeitos dos fármacos , Percepção Auditiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Medo/fisiologia , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Propranolol/farmacologia , Distribuição Aleatória , Ratos Long-Evans , Estresse Psicológico/metabolismo
10.
Front Behav Neurosci ; 9: 205, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26300750

RESUMO

Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.

11.
J Insect Physiol ; 67: 45-55, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24968146

RESUMO

The spatial distribution of proteolytic enzymes in the adult foregut of Protophormia terraenovae was studied in the context of protein digestion and regurgitation. Based on substrate specificity, pH optima, and use of specific protease inhibitors, all adults tested displayed enzyme activity in the foregut consistent with pepsin, trypsin and chymotrypsin. Chymotrypsin-like and trypsin-like enzyme activity were detected in all gut fluids and tissues tested, with chymotrypsin displaying the highest activity in saliva and salivary gland tissue, whereas maximal trypsin activity was evident in the crop. Pepsin-like activity was only evident in crop fluids and tissues. The activity of all three enzymes was low or undetectable (pepsin) in the fluids and tissue homogenates derived from the esophagus and cardia of any of the adults assayed. Fed adult females displayed higher enzyme activities than fed males, and the activity of all three enzymes were much more prevalent in fed adults than starved. The pH optimum of the trypsin-like enzyme was between pH 7.0 and 8.0; chymotrypsin was near pH 8.0; and maximal pepsin-like activity occurred between pH 1.0 and 2.0. Regurgitate from fed adult females displayed enzyme activity consistent with the proteolytic enzymes detected in crop gut fluids. Enzymes in regurgitate were not derived from food sources based on assays of bovine liver samples. These latter observations suggest that adult flies release fluids from foregut when encountering dry foods, potentially as a means to initiate extra-oral digestion.


Assuntos
Digestão/fisiologia , Dípteros/enzimologia , Endopeptidases/metabolismo , Trato Gastrointestinal/enzimologia , Saliva/enzimologia , Animais , Bovinos , Feminino , Concentração de Íons de Hidrogênio , Fígado/enzimologia , Masculino , Peptídeo Hidrolases , Inibidores de Proteases , Especificidade por Substrato
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