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1.
PLoS One ; 17(5): e0263546, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35507596

RESUMO

Model organisms mimicking the pathogenesis of human diseases are useful for identifying pathogenic mechanisms and testing therapeutic efficacy of compounds targeting them. Models of Alzheimer's disease (AD) and related dementias (ADRD) aim to reproduce the brain pathology associated with these neurodegenerative disorders. Transgenic models, which involve random insertion of disease-causing genes under the control of artificial promoters, are efficient means of doing so. There are confounding factors associated with transgenic approaches, however, including target gene overexpression, dysregulation of endogenous gene expression at transgenes' integration sites, and limitations in mimicking loss-of-function mechanisms. Furthermore, the choice of species is important, and there are anatomical, physiological, and cognitive reasons for favoring the rat over the mouse, which has been the standard for models of neurodegeneration and dementia. We report an initial assessment of the spatial learning, reversal, and sequencing task capabilities of knock-in (KI) Long-Evans rats with humanizing mutations in the Aß-coding region of App, which encodes amyloid precursor protein (Apph/h rats), using the IntelliCage, an automated operant social home cage system, at 6-8 weeks of age, then again at 4-5 months of age. These rats were previously generated as control organisms for studies on neurodegeneration involving other knock-in rat models from our lab. Apph/h rats of either sex can acquire place learning and reversal tasks. They can also acquire a diagonal sequencing task by 6-8 weeks of age, but not a more advanced serial reversal task involving alternating diagonals, even by 4-5 months of age. Thus, longitudinal behavioral analysis with the IntelliCage system can be useful to determine, in follow-up studies, whether KI rat models of Familial AD (FAD), sporadic late onset AD (LOAD), and of ADRD develop aging-dependent learning and memory deficits.


Assuntos
Doença de Alzheimer , Aplicativos Móveis , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Modelos Animais de Doenças , Camundongos Transgênicos , Mutação , Ratos , Ratos Long-Evans , Reversão de Aprendizagem
2.
Nutrients ; 14(8)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35458215

RESUMO

Prenatal alcohol exposure causes neurodevelopmental disability and is associated with a functional iron deficiency in the fetus and neonate, even when the mother consumes an apparently iron-adequate diet. Here, we test whether gestational administration of the clinically relevant iron supplement Fer-In-Sol mitigates alcohol's adverse impacts upon the fetus. Pregnant Long-Evans rats consumed an iron-adequate diet and received 5 g/kg alcohol by gavage for 7 days in late pregnancy. Concurrently, some mothers received 6 mg/kg oral iron. We measured maternal and fetal weights, hematology, tissue iron content, and oxidative damage on gestational day 20.5. Alcohol caused fetal anemia, decreased fetal body and brain weight, increased hepatic iron content, and modestly elevated hepatic malondialdehyde (p's < 0.05). Supplemental iron normalized this brain weight reduction in alcohol-exposed males (p = 0.154) but not female littermates (p = 0.031). Iron also reversed the alcohol-induced fetal anemia and normalized both red blood cell numbers and hematocrit (p's < 0.05). Iron had minimal adverse effects on the mother or fetus. These data show that gestational iron supplementation improves select fetal outcomes in prenatal alcohol exposure (PAE) including brain weight and hematology, suggesting that this may be a clinically feasible approach to improve prenatal iron status and fetal outcomes in alcohol-exposed pregnancies.


Assuntos
Ferro , Efeitos Tardios da Exposição Pré-Natal , Animais , Suplementos Nutricionais , Modelos Animais de Doenças , Etanol/farmacologia , Feminino , Feto , Humanos , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Ratos , Ratos Long-Evans
3.
Addict Biol ; 27(3): e13176, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35470561

RESUMO

There is growing evidence that immune signalling may be involved in both the causes and consequences of alcohol abuse. Toll-like receptor (TLR) expression is increased by alcohol consumption and is implicated in AUD, and specifically TLR7 may play an important role in ethanol consumption. We administered the TLR7-specific agonist imiquimod in male and female Long-Evans rats to determine (1) gene expression changes in brain regions involved in alcohol reinforcement, the nucleus accumbens core and anterior insular cortex, in rats with and without an alcohol history, and (2) whether TLR7 activation could modulate operant alcohol self-administration. Interferon regulatory factor 7 (IRF7) was dramatically increased in both sexes at both 2- and 24-h post-injection regardless of alcohol history and TLR3 and 7 gene expression was increased as well. The proinflammatory cytokine TNFα was increased 24-h post-injection in rats with an alcohol self-administration history, but this effect did not persist after four injections, suggesting molecular tolerance. Ethanol consumption was increased 24 h after imiquimod injections but did not occur until the third injection, suggesting adaptation to repeated TLR7 activation is necessary for increased drinking to occur. Notably, imiquimod reliably induced weight loss, indicating that sickness behaviour persisted across repeated injections. These findings show that TLR7 activation can modulate alcohol drinking in an operant self-administration paradigm and suggest that TLR7 and IRF7 signalling pathways may be a viable druggable target for treatment of AUD.


Assuntos
Etanol , Receptor 7 Toll-Like , Animais , Condicionamento Operante , Etanol/farmacologia , Feminino , Imiquimode/farmacologia , Masculino , Ratos , Ratos Long-Evans , Receptores Toll-Like
4.
Pharmacol Biochem Behav ; 216: 173379, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35395252

RESUMO

Toll-like receptor (TLR) signaling may play an important role in the neuroimmune system's involvement in the development and maintenance of alcohol use disorder (AUD). In the present study we administered the TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption on a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg. However, when 1.0 mg/kg was given on consecutive days, alcohol intake increased in the days following injections specifically in females. In a second experiment, we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final experiment the poly(I:C) dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions in alcohol intake on injection days in females that were not accompanied by subsequent increases. The poly(I:C) dose was increased to 9.0 mg/kg for one final pair of injections which led to reductions in intake in both males and females followed by a male specific delayed increase in alcohol intake. Overall, repeated poly(I:C) administration was able to increase subsequent alcohol consumption in both sexes, with females showing an increase at a lower dose than males. These findings support TLR3 agonism in contributing to increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.


Assuntos
Alcoolismo , Receptor 3 Toll-Like , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Alcoolismo/tratamento farmacológico , Animais , Etanol/farmacologia , Feminino , Hormônios Esteroides Gonadais , Masculino , Poli I-C/farmacologia , Ratos , Ratos Long-Evans , Autoadministração , Receptor 3 Toll-Like/agonistas
5.
Life Sci ; 298: 120504, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35367242

RESUMO

AIMS: Hyperinsulinemia is an important causative factor of prostate enlargement in type 2 diabetes (T2D), however, clinically prostate weight increases during hypoinsulinemic condition. To investigate the pathogenesis of prostate enlargement and effects of phosphodiesterase 5 inhibitor (PDE5i), male Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as T2D and control, respectively. MATERIALS AND METHODS: OLETF and LETO rats were treated with oral tadalafil (100 µg/kg/day) or vehicle for 12 wks from at the age of 36 wks. KEY FINDINGS: Prostate weight of OLETF rats was significantly higher than that of LETO at 36 wks, and increased at 48 wks. In OLETF rats, prostate blood flow was significantly lower at 48 wks versus 36 wks. Twelve-week-tadalafil treatment increased prostate blood flow and suppressed prostate weight increase in both strains. This change was inversely correlated with changes in prostate expressions of hypoxia-inducible factor-1 alpha (HIF-1α) and 8-hydroxy-2'-deoxyguanosine (8-OHdG). Increases with age were observed in mRNA and/or protein levels of cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-α) and cell growth factors insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and transforming growth factor-beta (TGF-ß); especially IL-6, TNF-α, IGF-1, bFGF and TGF-ß increased with T2D. Tadalafil suppressed these cytokines and growth factors. SIGNIFICANCE: These data suggest chronic ischemia caused by T2D leads to oxidative stress, resulting in prostate enlargement through upregulation of several cytokines and growth factors. Treatment with PDE5i improves prostate ischemia and might prevent enlargement via suppression of cytokines and growth factors in T2D.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Animais , Glicemia , Diabetes Mellitus Tipo 2/metabolismo , Fator de Crescimento Insulin-Like I , Masculino , Inibidores da Fosfodiesterase 5/farmacologia , Inibidores da Fosfodiesterase 5/uso terapêutico , Próstata/patologia , Ratos , Ratos Endogâmicos OLETF , Ratos Long-Evans , Tadalafila/farmacologia , Tadalafila/uso terapêutico , Fator de Crescimento Transformador beta , Fator de Necrose Tumoral alfa , Ganho de Peso
6.
PLoS One ; 17(4): e0266331, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35390035

RESUMO

Lingzhi has long been regarded as having life-prolonging effects. Research in recent years has also reported that Lingzhi possesses anti-tumor, anti-inflammatory, immunomodulatory, hepatoprotective, and anti-lipogenic effects. The D-galactose (D-gal, 100 mg/kg/day)-induced aging Long-Evans rats were simultaneously orally administered a DMSO extract of Ganoderma tsugae (GTDE, 200 µg/kg/day) for 25 weeks to investigate the effects of GTDE on oxidative stress and memory deficits in the D-galactose-induced aging rats. We found that GTDE significantly improved the locomotion and spatial memory and learning in the aging rats. GTDE alleviated the aging-induced reduction of dendritic branching in neurons of the hippocampus and cerebral cortex. Immunoblotting revealed a significant increase in the protein expression levels of the superoxide dismutase-1 (SOD-1) and catalase, and the brain-derived neurotrophic factor (BDNF) in rats that received GTDE. D-gal-induced increase in the lipid peroxidation product 4-hydroxynonenal (4-HNE) was significantly attenuated after the administration of GTDE, and pyrin domain-containing 3 protein (NLRP3) revealed a significant decrease in NLRP3 expression after GTDE administration. Lastly, GTDE significantly reduced the advanced glycosylation end products (AGEs). In conclusion, GTDE increases antioxidant capacity and BDNF expression of the brain, protects the dendritic structure of neurons, and reduces aging-induced neuronal damage, thereby attenuating cognitive impairment caused by aging.


Assuntos
Disfunção Cognitiva , Ganoderma , Envelhecimento/metabolismo , Animais , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Galactose/metabolismo , Galactose/toxicidade , Ganoderma/metabolismo , Aprendizagem em Labirinto , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Estresse Oxidativo , Ratos , Ratos Long-Evans
7.
Glycoconj J ; 39(1): 107-130, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35254602

RESUMO

Using a partial hippocampal cholinergic denervation model, we assessed the effects of the RGTA® named OTR4132, a synthetic heparan-mimetic biopolymer with neuroprotective/neurotrophic properties. Long-Evans male rats were injected with the cholinergic immunotoxin 192 IgG-saporin into the medial septum/diagonal band of Broca (0.37 µg); vehicle injections served as controls. Immediately after surgery, OTR4132 was injected into the lateral ventricles (0.25 µg/5 µl/rat) or intramuscularly (1.5 mg/kg). To determine whether OTR4132 reached the lesion site, some rats received intracerebroventricular (ICV) or intramuscular (I.M.) injections of fluorescent OTR4132. Rats were sacrificed at 4, 10, 20, or 60 days post-lesion (DPL). Fluorescein-labeled OTR4132 injected ICV or I.M. was found in the lesion from 4 to 20 DPL. Rats with partial hippocampal cholinergic denervation showed decreases in hippocampal acetylcholinesterase reaction products and in choline acetyltransferase-positive neurons in the medial septum. These lesions were the largest at 10 DPL and then remained stable until 60 DPL. Both hippocampal acetylcholinesterase reaction products and choline acetyltransferase-positive neurons in the medial septum effects were significantly attenuated in OTR4132-treated rats. These effects were not related to competition between OTR4132 and 192 IgG-saporin for the neurotrophin receptor P75 (p75NTR), as OTR4132 treatment did not alter the internalization of Cy3-labelled 192 IgG. OTR4132 was more efficient at reducing the acetylcholinesterase reaction products and choline acetyltransferase-positive neurons than a comparable heparin dose used as a comparator. Using the slice superfusion technique, we found that the lesion-induced decrease in muscarinic autoreceptor sensitivity was abolished by intramuscular OTR4132. After partial cholinergic damage, OTR4132 was able to concentrate at the brain lesion site possibly due to the disruption of the blood-brain barrier and to exert structural and functional effects that hold promises for neuroprotection/neurotrophism.


Assuntos
Acetilcolinesterase , Glicosaminoglicanos , Animais , Colinérgicos/farmacologia , Glicosaminoglicanos/farmacologia , Masculino , Ratos , Ratos Long-Evans , Proteínas Inativadoras de Ribossomos Tipo 1
8.
J Neurosci ; 42(18): 3811-3822, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35351827

RESUMO

The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been associated with the expression of adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, reported effects of mPFC manipulations on cue-elicited natural reward-seeking and inhibition thereof have been varied, with few studies examining cortico-striatal contributions in tasks that require adaptive responding to cues signaling reward and punishment within the same session. The current study aimed to better elucidate the role of mPFC and NAc subdivisions, and their functional connectivity in cue-elicited adaptive responding using a novel discriminative cue responding task. Male Long-Evans rats learned to lever-press on a VR5 schedule for a discriminative cue signaling reward, and to avoid pressing the same lever in the presence of another cue signaling punishment. Postacquisition, prelimbic (PL) and infralimbic (IL) areas of the mPFC, NAc core, shell, PL-core, or IL-shell circuits were pharmacologically or chemogenetically inhibited while animals performed under (1) nonreinforced (extinction) conditions, where the appetitive and aversive cues were presented in alternating trials alone or as a compound stimulus; and (2) reinforced conditions, whereby cued responding was accompanied by associated outcomes. PL and IL inactivation attenuated nonreinforced and reinforced goal-directed cue responding, whereas NAc core and shell inactivation impaired nonreinforced responding for the appetitive, but not aversive cue. Furthermore, PL-core and IL-shell inhibition disinhibited nonreinforced but not reinforced cue responding. Our findings implicate the mPFC as a site of confluence of motivationally significant cues and outcomes, and in the regulation of nonreinforced cue responding via downstream NAc targets.SIGNIFICANCE STATEMENT The ability to discriminate and respond appropriately to environmental cues that signal availability of reward or punishment is essential for survival. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) have been implicated in adaptive and maladaptive behavior elicited by fear-related and drug-associated cues. However, less is known about the role they play in orchestrating adaptive responses to natural reward and punishment cues within the same behavioral task. Here, using a novel discriminative cue responding task combined with pharmacological or chemogenetic inhibition of mPFC, NAc and mPFC-NAc circuits, we report that mPFC is critically involved in responding to changing cued response-outcomes, both when the responses are reinforced, and nonreinforced. Furthermore, the mPFC coordinates nonreinforced discriminative cue responding by suppressing inappropriate responding via downstream NAc targets.


Assuntos
Sinais (Psicologia) , Punição , Animais , Condicionamento Operante/fisiologia , Objetivos , Masculino , Núcleo Accumbens , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Long-Evans , Recompensa , Sacarose/farmacologia
9.
Biol Psychiatry ; 91(9): 832-840, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35246314

RESUMO

BACKGROUND: In both rodents and humans, the basolateral amygdala (BLA) is essential for encoding and retrieving conditioned fear memories. Although the BLA is a putative storage site for these memories, recent evidence suggests that they become independent of the BLA with the passage of time. METHODS: We systematically examined the role for the BLA in the retrieval of recent (1 day) and remote (2 weeks) fear memory using optogenetic, electrophysiological, and calcium imaging methods in male and female Long-Evans rats. Critically, we used a behavioral design that permits within-subjects comparison of recent and remote memory at the same time point; freezing behavior served as the index of learned fear. RESULTS: We found that BLA c-Fos expression was similar after the retrieval of recent or remote fear memories. Extracellular single-unit recordings in awake, behaving animals revealed that single BLA neurons exhibit robust increases in spike firing to both recent and remote conditioned stimuli. Fiber photometry recordings revealed that these patterns of activity emerge from principal neurons. Consistent with these results, optogenetic inhibition of BLA principal neurons impaired conditioned freezing to both recent and remote conditioned stimuli. There were no sex differences in any of the measures or manipulations. CONCLUSIONS: These data reveal that BLA neurons encode both recent and remote fear memories, suggesting substantial overlap in the allocation of temporally distinct events. This may underlie the broad generalization of fear memories across both space and time. Ultimately, these results provide evidence that the BLA is a long-term storage site for emotional memories.


Assuntos
Complexo Nuclear Basolateral da Amígdala , Tonsila do Cerebelo/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Medo/fisiologia , Feminino , Humanos , Masculino , Memória de Longo Prazo , Ratos , Ratos Long-Evans
10.
Brain Res ; 1785: 147885, 2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35307330

RESUMO

The insula has become a significant brain region in the study of both normal and impaired behavior and decision-making and has emerged as an important contributor to drug addiction. Consistent with this literature, in a previous study, we found that neural signals in rat insula encode anticipation and contextual global reward value during performance of an odor-guided delay/size choice task, and that these signals are disrupted by prior cocaine self-administration. Still, it is unknown if insula is critical for performance of this task under normal circumstances. Here, we sought to elucidate the functional role of these signals by lesioning the same region of anterior insula we previously recorded from. In addition to examining behavior during decision-making, we characterized behavior during autoshaping to further assess insula's role in behavior. We found insula damage resulted in reduced accuracy and faster reaction times, without affecting rats' choice of high-value reward, and that insula lesions reduced sign-tracking behavior. These results suggest that insula contributes to our odor-guided delay/size choice task via mechanisms that impact the control that environmental stimuli have on behavior.


Assuntos
Cocaína , Odorantes , Animais , Comportamento de Escolha , Tomada de Decisões , Ratos , Ratos Long-Evans , Recompensa
11.
Dev Psychobiol ; 64(3): e22231, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35312054

RESUMO

Exposure to adversity in early development has powerful and potentially lasting consequences on behavior. Previous work in our laboratory using female Long-Evans rats has demonstrated that exposure to early-life maltreatment manifests into alterations in dam behavior, including a perpetuation of the maltreatment phenotype. These observed behavioral changes coincide with changes in epigenetic activity in the prefrontal cortex (PFC). Further, treating dams with a chromatin modifying agent (Zebularine) normalizes methylation and maltreatment phenotypes, suggesting a link between epigenetic programming and phenotypic outcomes. Here, we sought to investigate if administration of a chromatin modifying agent concurrent with the experience of maltreatment normalizes epigenetic activity associated with maltreatment and alters behavioral trajectories. Administration of valproic acid (VPA) transiently lowered levels of global DNA methylation in the PFC, regardless of exposure to nurturing care or maltreatment. When VPA-exposed animals reached adulthood, they engaged in more adverse behaviors toward their offspring. These data provide further evidence linking epigenetic changes in the developing brain with effects on behavior.


Assuntos
Metilação de DNA , Ácido Valproico , Adulto , Animais , Animais Recém-Nascidos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Feminino , Humanos , Comportamento Materno , Ratos , Ratos Long-Evans , Ácido Valproico/farmacologia
12.
Endocrinol Metab (Seoul) ; 37(2): 221-232, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35316888

RESUMO

BACKGROUND: Obesity, the prevalence of which is increasing due to the lack of exercise and increased consumption of Westernized diets, induces various complications, including ophthalmic diseases. For example, obesity is involved in the onset of cataracts. METHODS: To clarify the effects and mechanisms of midodrine, an α1-adrenergic receptor agonist, in cataracts induced by obesity, we conducted various analytic experiments in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a rat model of obesity. RESULTS: Midodrine prevented cataract occurrence and improved lens clearance in OLETF rats. In the lenses of OLETF rats treated with midodrine, we observed lower levels of aldose reductase, tumor necrosis factor-α, and sorbitol, but higher levels of hexokinase, 5'-adenosine monophosphate-activated protein kinase-alpha, adenosine 5´-triphosphate, peroxisome proliferator-activated receptordelta, peroxisome proliferator-activated receptor gamma coactivator 1-alpha, superoxide dismutase, and catalase. CONCLUSION: The ameliorating effects of midodrine on cataracts in the OLETF obesity rat model are exerted via the following three mechanisms: direct inhibition of the biosynthesis of sorbitol, which causes cataracts; reduction of reactive oxygen species and inflammation; and (3) stimulation of normal aerobic glycolysis.


Assuntos
Catarata , Midodrina , Animais , Catarata/tratamento farmacológico , Catarata/etiologia , Catarata/prevenção & controle , Glicólise , Midodrina/uso terapêutico , Obesidade/complicações , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ratos , Ratos Endogâmicos OLETF , Ratos Long-Evans , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos/uso terapêutico , Sorbitol/uso terapêutico
13.
Physiol Behav ; 248: 113726, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35122825

RESUMO

Predator odors provide critical information to prey species allowing them to gage potential threat via the detection of semiochemicals called kairomones. Recent reports indicate that the commercially available predator odor coyote urine (CU), and to a lesser extent 2-phenylethylamine (PEA), induce innate defensive behaviors in adult rats and mice. The aim of the present study was to see if the defense-inducing effects of CU and PEA would extend to adolescents. Specifically, we evaluated the ability of CU and PEA to induce unconditioned and conditioned defensive behavior in predator-odor naïve adolescent male and female Long-Evans hooded rats. An additional group of males were exposed to the non-predatory aversive odor formalin to control for potential general aversive properties of the odorants. The data revealed that in males, both CU and PEA, but not formalin induced measures of risk assessment, whereas CU and formalin produced avoidance of the odor source. In partial contrast, both CU and PEA produced avoidance of the odor source and increased measures of risk assessment in females. Surprisingly males failed to show any measures of defense during the cue+context conditioning test trial. In contrast, in females both odorants produced marginal effects during re-exposure to the conditioning context, with CU inducing conditioned avoidance and PEA inducing conditioned risk assessment. We conclude that commercially available CU and PEA elicit a moderate defensive profile compared to previous reports examining cat fur/skin odor in male and female adolescent rats. Future research needs to examine additional concentrations of the odorants to determine if a more robust unconditioned defensive profile (e.g., freezing) can be induced by these predator odors, and whether the defensive profile responds to standard anxiolytic drugs.


Assuntos
Coiotes , Animais , Comportamento Animal , Condicionamento Psicológico , Cobre/farmacologia , Feminino , Formaldeído , Masculino , Camundongos , Odorantes , Fenetilaminas , Comportamento Predatório , Ratos , Ratos Long-Evans
14.
J Neurosci ; 42(11): 2282-2297, 2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35110389

RESUMO

Running direction in the hippocampus is encoded by rate modulations of place field activity but also by spike timing correlations known as theta sequences. Whether directional rate codes and the directionality of place field correlations are related, however, has so far not been explored, and therefore the nature of how directional information is encoded in the cornu ammonis remains unresolved. Here, using a previously published dataset that contains the spike activity of rat hippocampal place cells in the CA1, CA2, and CA3 subregions during free foraging of male Long-Evans rats in a 2D environment, we found that rate and spike timing codes are related. Opposite to a preferred firing rate direction of a place field, spikes are more likely to undergo theta phase precession and, hence, more strongly affect paired correlations. Furthermore, we identified a subset of field pairs whose theta correlations are intrinsic in that they maintain the same firing order when the running direction is reversed. Both effects are associated with differences in theta phase distributions and are more prominent in CA3 than in CA1. We thus hypothesize that intrinsic spiking is most prominent when the directionally modulated sensory-motor drive of hippocampal firing rates is minimal, suggesting that extrinsic and intrinsic sequences contribute to phase precession as two distinct mechanisms.SIGNIFICANCE STATEMENT Hippocampal theta sequences, on the one hand, are thought to reflect the running trajectory of an animal, connecting past and future locations. On the other hand, sequences have been proposed to reflect the rich, recursive hippocampal connectivity, related to memories of previous trajectories or even to experience-independent prestructure. Such intrinsic sequences are inherently one dimensional and cannot be easily reconciled with running trajectories in two dimensions as place fields can be approached on multiple one-dimensional paths. In this article, we dissect phase precession along different directions in all hippocampal subareas and find that CA3 in particular shows a high level of direction-independent correlations that are inconsistent with the notion of representing running trajectories. These intrinsic correlations are associated with later spike phases.


Assuntos
Células de Lugar , Ritmo Teta , Potenciais de Ação , Animais , Hipocampo , Masculino , Modelos Neurológicos , Ratos , Ratos Long-Evans
15.
J Neurosci ; 42(13): 2743-2755, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35135853

RESUMO

The medial orbitofrontal cortex (mOFC) regulates a variety of cognitive functions, including refining action selection involving reward uncertainty. This region sends projections to numerous subcortical targets, including the ventral and dorsal striatum, yet how these corticostriatal circuits differentially regulate risk/reward decision-making is unknown. The present study examined the contribution of mOFC circuits linking the nucleus accumbens (NAc) and dorsomedial striatum (DMS) to risk/reward decision-making using pharmacological disconnections. Male rats were well trained on a probabilistic discounting task involving choice between small/certain or large/risky rewards, with the probability of obtaining the larger reward decreasing or increasing over a session. Disconnection of mOFC-striatal pathways was achieved using infusions of GABA agonists inactivating the mOFC in one hemisphere, combined with NAc or DMS inactivation in the contralateral or ipsilateral hemisphere. Perturbing mOFC → NAc circuits induced suboptimal, near-random patterns of choice that manifested as a flattening of the discounting curve. Animals were equally likely to stay or shift following rewarded/nonrewarded choices, suggesting this pathway mediates use of information about reward history to stabilize decision biases. In contrast, mOFC → DMS disconnection impaired adjustments in decision biases, causing opposing changes in risky choice depending on how probabilities varied over time. This was driven by alterations in lose-shift behavior, suggesting mOFC → DMS circuits track volatility in nonrewarded actions to adjust choice in accordance with changes in profitability. Thus, separate mOFC-striatal projection pathways regulate dissociable processes underlying decision-making, with mOFC → NAc circuits aiding in establishing and stabilizing tasks states and mOFC → DMS circuits facilitating transitions across states to promote flexible reward seeking.SIGNIFICANCE STATEMENT The medial orbitofrontal cortex regulates a variety of goal-directed behaviors, yet the functional circuits through which it mediates higher order decision-making functions are unclear. The present study revealed that different mOFC projection pathways facilitate diverse aspects of decision-making involving risks and rewards by engaging separate networks of neurons that interface with distinct ventral and dorsal striatal targets. These findings clarify some of the normal functions of these corticostriatal pathways and may have implications for understanding how dysfunction in these circuits relate to certain psychiatric disorders.


Assuntos
Tomada de Decisões , Recompensa , Animais , Corpo Estriado , Tomada de Decisões/fisiologia , Humanos , Masculino , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Long-Evans
16.
Behav Processes ; 196: 104602, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35124157

RESUMO

Although both human and non-human animals, in everyday life, deal with risky decisions in a social environment, few studies investigated how social dimension influences risk preferences (i.e., if consequences on others feeds back over own choice). Here, we assessed whether the presence of a conspecific, acting as a potential competitor for the same food resource, influenced risky decision-making in male rats. Subjects received a series of choices between a safe option (always yielding a small yet optimal reward, solely to itself) and a risky option (yielding a larger but suboptimal reward, one third of times to itself and two third of times delivered to the other half cage); rats were tested twice, both alone and paired with a conspecific, recipient of own-lost food and hence acting as potential competitor. Results showed that focal subjects were more risk-prone when paired with a conspecific than when tested alone. However, rats exhibited also a higher motivational conflict with a competing bystander present than alone: data suggest that the primary drive was to increase "own" food rather than either a competitive or prosocial tendency. Overall, for rats tested in a risky-choice task, a competitive social context increased the salience and attractiveness of larger food outcomes, as observed in humans and great apes. This led to the economically irrational response of selecting the "binge-but-risky" option, notwithstanding uncertainty about the actual recipient of such food.


Assuntos
Recompensa , Assunção de Riscos , Animais , Comportamento de Escolha/fisiologia , Tomada de Decisões/fisiologia , Masculino , Ratos , Ratos Long-Evans
17.
J Integr Neurosci ; 21(1): 12, 2022 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-35164448

RESUMO

Objective: In the framework of a larger project aiming to test putative cognitive enhancer drugs in a system with improved translational validity, we established a rodent test battery, where different, clinically relevant cognitive domains were investigated in the same animal population. The aim of the current study was to check whether performances in the different tasks representing different cognitive functions are assay-specific or may originate in an underlying general learning ability factor. Methods: In the experiments 36 Long-Evans and 36 Lister Hooded rats were used. The test battery covered the following cognitive domains: attention and impulsivity (measured in the 5-choice serial reaction time task), spatial memory (Morris water-maze), social cognition (cooperation task), cognitive flexibility (attentional set shifting test), recognition memory (novel object recognition) and episodic memory (water-maze based assay). The outcome variables were analyzed by correlation analysis and principal component analysis (PCA). The datasets consisted of variables measuring learning speed and performance in the paradigms. From the raw variables composite variables were created for each assay, then from these variables a composite score was calculated describing the overall performance of each individual in the test battery. Results: Correlations were only found among the raw variables characterizing the same assay but not among variables belonging to different tests or among the composite variables. The PCAs did not reduce the dimensionality of the raw or composite datasets. Graphical analysis showed variable performance of the animals in the applied tests. Conclusions: The results suggests the assay outcomes (learning performance) in the system are based on independent cognitive domains.


Assuntos
Atenção/fisiologia , Cognição/fisiologia , Função Executiva/fisiologia , Aprendizagem/fisiologia , Desempenho Psicomotor/fisiologia , Cognição Social , Animais , Comportamento Animal/fisiologia , Testes Neuropsicológicos , Análise de Componente Principal , Ratos , Ratos Long-Evans
18.
Elife ; 112022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35142608

RESUMO

Vibrissa sensory inputs play a central role in driving rodent behavior. These inputs transit through the sensory trigeminal nuclei, which give rise to the ascending lemniscal and paralemniscal pathways. While lemniscal projections are somatotopically mapped from brainstem to cortex, those of the paralemniscal pathway are more widely distributed. Yet the extent and topography of paralemniscal projections are unknown, along with the potential role of these projections in controlling behavior. Here, we used viral tracers to map paralemniscal projections. We find that this pathway broadcasts vibrissa-based sensory signals to brainstem regions that are involved in the regulation of autonomic functions and to forebrain regions that are involved in the expression of emotional reactions. We further provide evidence that GABAergic cells of the Kölliker-Fuse nucleus gate trigeminal sensory input in the paralemniscal pathway via a mechanism of presynaptic or extrasynaptic inhibition.


Assuntos
Vias Aferentes/fisiologia , Tronco Encefálico/fisiologia , Sistema Límbico/fisiologia , Núcleos do Trigêmeo/fisiologia , Vibrissas/fisiologia , Animais , Eletrofisiologia , Optogenética , Ratos , Ratos Long-Evans
19.
Behav Brain Res ; 423: 113790, 2022 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-35149121

RESUMO

Evidence from genetic, behavioural, anatomical, and physiological study suggests that the hippocampus functionally differs across its longitudinal (dorsoventral or septotemporal) axis. Although, how to best characterize functional and representational differences in the hippocampus across its long axis remains unclear. While some suggest that the hippocampus can be divided into dorsal and ventral subregions that support distinct cognitive functions, others posit that these regions vary in their granularity of representation, wherein spatial-temporal resolution decreases in the ventral (temporal) direction. Importantly, the cognitive and granular hypotheses also make distinct predictions on cellular recruitment dynamics under conditions when animals perform tasks with qualitatively different cognitive-behavioural demands. One interpretation of the cognitive function account implies that dorsal and ventral cellular recruitment differs depending on relevant behavioural demands, while the granularity account suggests similar recruitment dynamics regardless of the nature of the task performed. Here, we quantified cellular recruitment with the immediate early gene (IEG) Arc across the entire longitudinal CA1 axis in female and male rats performing spatial- and fear-guided memory tasks. Our results show that recruitment is greater in dorsal than ventral CA1 regardless of task or sex, and thus support a granular view of hippocampal function across the long axis. We further discuss how future experiments might determine the relative contributions of cognitive function and granularity of representation to neuronal activity dynamics in hippocampal circuits.


Assuntos
Comportamento Animal/fisiologia , Região CA1 Hipocampal/metabolismo , Proteínas do Citoesqueleto/metabolismo , Aprendizagem/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Animais , Feminino , Masculino , Ratos , Ratos Long-Evans , Caracteres Sexuais , Análise e Desempenho de Tarefas
20.
Neuroimage ; 250: 118960, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35121182

RESUMO

The blood oxygenation level-dependent (BOLD)-based resting-state functional magnetic resonance imaging (rsfMRI) has been widely used as a non-invasive tool to map brain-wide connectivity architecture. However, the neural basis underpinning the resting-state BOLD signal remains elusive. In this study, we combined simultaneous calcium-based fiber photometry with rsfMRI in awake animals to examine the relationship of the BOLD signal and spiking activity at the resting state. We observed robust couplings between calcium and BOLD signals in the dorsal hippocampus as well as other distributed areas in the default mode network (DMN), suggesting that the calcium measurement can reliably predict the rsfMRI signal. In addition, using the calcium signal recorded as the ground truth, we assessed the impacts of different rsfMRI data preprocessing pipelines on functional connectivity mapping. Overall, our results provide important evidence suggesting that spiking activity measured by the calcium signal plays a key role in the neural mechanism of resting-state BOLD signal.


Assuntos
Cálcio/metabolismo , Rede de Modo Padrão/diagnóstico por imagem , Rede de Modo Padrão/metabolismo , Imageamento por Ressonância Magnética/métodos , Animais , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Processamento de Imagem Assistida por Computador , Masculino , Ratos , Ratos Long-Evans
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