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1.
FASEB J ; 37(12): e23322, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37983662

RESUMEN

Recent studies have shown that the non-DA neurons in the ventral tegmental area (VTA) and substantia nigra (SN) not only modulate motivational behaviors but also regulate defensive behaviors. While zona incerta (ZI) is a threat-responsive substrate and receives innervations from the ventral midbrain, the function of the ventral midbrain-to-ZI connection remains poorly defined. Here, we demonstrate that the ZI receives heterogenous innervations from the ventral midbrain. By utilizing a retrograde AAV preferentially labeling non-DA neurons in the ventral midbrain, we found that ZI-projecting non-DA cells in the ventral midbrain are activated by restraint stress. We focused on the SN and found that SN-to-ZI GABAergic input is engaged by a predatory odor. Sustained pan-neuronal SN-to-ZI activation results in aversion and enhances defensive behaviors, likely through a disinhibition mechanism to recruit downstream brain regions that regulate defensive behaviors. Collectively, our results reveal a novel role of nigroincertal projection in mediating negative valence and regulating defensive behaviors.


Asunto(s)
Neuronas , Sustancia Negra , Adaptación Psicológica , Área Tegmental Ventral
2.
J Neurosci ; 43(44): 7276-7293, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37684032

RESUMEN

The parabrachial nucleus (PBN) interfaces between taste and feeding systems and is also an important hub for relaying distress information and threats. Despite that the PBN sends projections to the ventral tegmental area (VTA), a heterogeneous brain region that regulates motivational behaviors, the function of the PBN-to-VTA connection remains elusive. Here, by using male mice in several behavioral paradigms, we discover that VTA-projecting PBN neurons are significantly engaged in contextual fear, restraint or mild stress but not palatable feeding, visceral malaise, or thermal pain. These results suggest that the PBN-to-VTA input may relay negative emotions under threat. Consistent with this notion, optogenetic activation of PBN-to-VTA glutamatergic input results in aversion, which is sufficient to override palatable feeding. Moreover, in a palatable food-reinforced operant task, we demonstrate that transient optogenetic activation of PBN-to-VTA input during food reward retrieval disengages instrumental food-seeking behaviors but spares learned action-outcome association. By using an activity-dependent targeting approach, we show that VTA DA neurons are disengaged by the PBN afferent activation, implicating that VTA non-DA neurons may mediate PBN afferent regulation. We further show that optogenetic activation of VTA neurons functionally recruited by the PBN input results in aversion, dampens palatable feeding, and disengages palatable food self-administration behavior. Finally, we demonstrate that transient activation of VTA glutamatergic, but not GABAergic, neurons recapitulates the negative regulation of the PBN input on food self-administration behavior. Together, we reveal that the PBN-to-VTA input conveys negative affect, likely through VTA glutamatergic neurons, to disengage instrumental food-seeking behaviors.SIGNIFICANCE STATEMENT The PBN receives multiple inputs and thus is well positioned to route information of various modalities to engage different downstream circuits to attend or respond accordingly. We demonstrate that the PBN-to-VTA input conveys negative affect and then triggers adaptive prioritized responses to address pertinent needs by withholding ongoing behaviors, such as palatable food seeking or intake shown in the present study. It has evolutionary significance because preparing to cope with stressful situations or threats takes priority over food seeking to promote survival. Knowing how appropriate adaptive responses are generated will provide new insights into circuitry mechanisms of various coping behaviors to changing environmental stimuli.


Asunto(s)
Núcleos Parabraquiales , Área Tegmental Ventral , Ratones , Masculino , Animales , Área Tegmental Ventral/fisiología , Núcleos Parabraquiales/fisiología , Alimentos , Neuronas GABAérgicas , Emociones , Recompensa
3.
J Physiol ; 598(18): 4003-4029, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32598024

RESUMEN

KEY POINTS: The locus coeruleus (LC) contains noradrenergic (NA) neurons that respond to novel stimuli in the environment with phasic activation to initiate an orienting response; phasic LC activation is also triggered by stimuli, representing the outcome of task-related decision processes, to facilitate ensuing behaviours and help optimize task performance. Here, we report that LC-NA neurons exhibit bursts of action potentials in vitro resembling phasic LC activation in vivo, and the activity is gated by inhibitory interneurons (I-INs) located in the peri-LC. We also observe that inhibition of peri-LC I-INs enhances prepulse inhibition and axons from cortical areas that play important roles in evaluating the cost/reward of a stimulus synapse on both peri-LC I-INs and LC-NA neurons. The results help us understand the cellular mechanisms underlying the generation and regulation of phasic LC activation with a focus on the role of peri-LC I-INs. ABSTRACT: Noradrenergic (NA) neurons in the locus coeruleus (LC) have global axonal projection to the brain. These neurons discharge action potentials phasically in response to either novel stimuli in the environment to initiate an orienting behaviour or stimuli representing the outcome of task-related decision processes to facilitate ensuing behaviours and help optimize task performance. Nevertheless, the cellular mechanisms underlying the generation and regulation of phasic LC activation remain unknown. We report here that LC-NA neurons recorded in brain slices exhibit bursts of action potentials that resembled the phasic activation-pause profile observed in animals. The activity was referred to as phasic-like activity (PLA) and was suppressed and enhanced by blocking excitatory and inhibitory synaptic transmissions, respectively. These results suggest the existence of a local circuit to drive PLA, and the activity could be regulated by the excitatory-inhibitory balance of the circuit. In support of this notion, we located a population of inhibitory interneurons (I-INs) in the medial part of the peri-LC that exerted feedforward inhibition of LC-NA neurons through GABAergic and glycinergic transmissions. Selective inhibition of peri-LC I-INs with chemogenetic methods could enhance PLA in brain slices and increase prepulse inhibition in animals. Moreover, axons from the orbitofrontal and prelimbic cortices, which play important roles in evaluating the cost/reward of a stimulus, synapse on both peri-LC I-INs and LC-NA neurons. These observations demonstrate functional roles of peri-LC I-INs in integrating inputs of the frontal cortex onto LC-NA neurons and gating the phasic LC output.


Asunto(s)
Neuronas Adrenérgicas , Locus Coeruleus , Potenciales de Acción , Animales , Interneuronas , Ratones , Norepinefrina
4.
J Biomed Sci ; 24(1): 69, 2017 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-28877723

RESUMEN

BACKGROUND: Long-term potentiation (LTP) is well recognized as a cellular-correlated synaptic plasticity of learning and memory. However, its reversal forms of synaptic plasticity, depotentiation, is less studied and its association with behaviors is also far from clear. Previously, we have shown that nanomolar orexin A can prevent the depotentiation induced by low frequency stimulation (LFS) following theta burst stimulation-induced LTP, namely inducing re-potentiation, at hippocampal CA1 synapses in vitro. Here, we explored the functional correlate of this orexin-mediated hippocampal re-potentiation. METHODS AND RESULTS: We found that intraperitoneal (i.p.) injection process-paired contextual exposures during the conditioned place preference (CPP) task in mice resulted in re-potentiation at CA1 synapses of hippocampal slices, regardless of whether the CPP behavior is expressed or not. Simply exposing the mouse in the CPP apparatus, or giving the mouse consecutive i.p. injections of saline in its home cage or a novel cage did not lead to hippocampal re-potentiation. Besides, this CPP training process-induced hippocampal re-potentiation was prevented when mice were pretreated with TCS1102, a dual orexin receptor antagonist. These results suggest that the expression of hippocampal re-potentiation is orexin-dependent and requires the association of differential spatial contexts and i.p. injections in the CPP apparatus. CONCLUSIONS: Together, we reveal an unprecedentedly orexin-mediated modulation on hippocampal depotentiation by the training process in the CPP paradigm.


Asunto(s)
Hipocampo/fisiología , Potenciación a Largo Plazo , Depresión Sináptica a Largo Plazo , Orexinas/metabolismo , Animales , Condicionamiento Clásico , Masculino , Ratones , Ratones Endogámicos C57BL
5.
Neuron ; 93(2): 425-440, 2017 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-28103482

RESUMEN

Fear learning is a fundamental behavioral process that requires dopamine (DA) release. Experience-dependent synaptic plasticity occurs on DA neurons while an organism is engaged in aversive experiences. However, whether synaptic plasticity onto DA neurons is causally involved in aversion learning is unknown. Here, we show that a stress priming procedure enhances fear learning by engaging VTA synaptic plasticity. Moreover, we took advantage of the ability of the ATPase Thorase to regulate the internalization of AMPA receptors (AMPARs) in order to selectively manipulate glutamatergic synaptic plasticity on DA neurons. Genetic ablation of Thorase in DAT+ neurons produced increased AMPAR surface expression and function that lead to impaired induction of both long-term depression (LTD) and long-term potentiation (LTP). Strikingly, animals lacking Thorase in DAT+ neurons expressed greater associative learning in a fear conditioning paradigm. In conclusion, our data provide a novel, causal link between synaptic plasticity onto DA neurons and fear learning.


Asunto(s)
Aprendizaje por Asociación/fisiología , Dopamina/metabolismo , Neuronas Dopaminérgicas/fisiología , Miedo , Plasticidad Neuronal/fisiología , Estrés Psicológico , ATPasas Asociadas con Actividades Celulares Diversas , Adenosina Trifosfatasas/genética , Adenosina Trifosfatasas/metabolismo , Animales , Conducta Animal , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Técnicas de Inactivación de Genes , Captura por Microdisección con Láser , Aprendizaje/fisiología , Potenciación a Largo Plazo/fisiología , Depresión Sináptica a Largo Plazo/fisiología , Ratones , Técnicas de Placa-Clamp , Receptores AMPA/metabolismo , Área Tegmental Ventral
6.
Cell Rep ; 16(10): 2699-2710, 2016 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-27568569

RESUMEN

The ventral tegmental area (VTA) receives phenotypically distinct innervations from the pedunculopontine tegmental nucleus (PPTg). While PPTg-to-VTA inputs are thought to play a critical role in stimulus-reward learning, direct evidence linking PPTg-to-VTA phenotypically distinct inputs in the learning process remains lacking. Here, we used optogenetic approaches to investigate the functional contribution of PPTg excitatory and inhibitory inputs to the VTA in appetitive Pavlovian conditioning. We show that photoinhibition of PPTg-to-VTA cholinergic or glutamatergic inputs during cue presentation dampens the development of anticipatory approach responding to the food receptacle during the cue. Furthermore, we employed in vivo optetrode recordings to show that photoinhibition of PPTg cholinergic or glutamatergic inputs significantly decreases VTA non-dopamine (non-DA) neural activity. Consistently, photoinhibition of VTA non-DA neurons disrupts the development of cue-elicited anticipatory approach responding. Taken together, our study reveals a crucial regulatory mechanism by PPTg excitatory inputs onto VTA non-DA neurons during appetitive Pavlovian conditioning.


Asunto(s)
Apetito/fisiología , Condicionamiento Clásico/fisiología , Neuronas Dopaminérgicas/fisiología , Aprendizaje , Núcleo Tegmental Pedunculopontino/fisiología , Área Tegmental Ventral/fisiología , Animales , Apetito/efectos de la radiación , Condicionamiento Clásico/efectos de la radiación , Señales (Psicología) , Neuronas Dopaminérgicas/efectos de la radiación , Glutamatos/metabolismo , Luz , Masculino , Ratones Endogámicos C57BL , Núcleo Tegmental Pedunculopontino/efectos de la radiación , Recompensa , Área Tegmental Ventral/efectos de la radiación
7.
Nat Neurosci ; 19(1): 111-6, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26642092

RESUMEN

Correlative studies have strongly linked phasic changes in dopamine activity with reward prediction error signaling. But causal evidence that these brief changes in firing actually serve as error signals to drive associative learning is more tenuous. Although there is direct evidence that brief increases can substitute for positive prediction errors, there is no comparable evidence that similarly brief pauses can substitute for negative prediction errors. In the absence of such evidence, the effect of increases in firing could reflect novelty or salience, variables also correlated with dopamine activity. Here we provide evidence in support of the proposed linkage, showing in a modified Pavlovian over-expectation task that brief pauses in the firing of dopamine neurons in rat ventral tegmental area at the time of reward are sufficient to mimic the effects of endogenous negative prediction errors. These results support the proposal that brief changes in the firing of dopamine neurons serve as full-fledged bidirectional prediction error signals.


Asunto(s)
Conducta Animal/fisiología , Condicionamiento Clásico/fisiología , Neuronas Dopaminérgicas/fisiología , Inhibición Neural/fisiología , Optogenética , Recompensa , Área Tegmental Ventral/fisiología , Animales , Anticipación Psicológica/fisiología , Fenómenos Electrofisiológicos , Femenino , Masculino , Ratas , Ratas Long-Evans , Ratas Transgénicas
8.
Nat Neurosci ; 18(5): 728-35, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25867120

RESUMEN

Sharp wave-associated field oscillations (∼200 Hz) of the hippocampus, referred to as ripples, are believed to be important for consolidation of explicit memory. Little is known about how ripples are regulated by other brain regions. We found that the median raphe region (MnR) is important for regulating hippocampal ripple activity and memory consolidation. We performed in vivo simultaneous recording in the MnR and hippocampus of mice and found that, when a group of MnR neurons was active, ripples were absent. Consistently, optogenetic stimulation of MnR neurons suppressed ripple activity and inhibition of these neurons increased ripple activity. Notably, using a fear conditioning procedure, we found that photostimulation of MnR neurons interfered with memory consolidation. Our results demonstrate a critical role of the MnR in regulating ripples and memory consolidation.


Asunto(s)
Mapeo Encefálico , Ondas Encefálicas/fisiología , Hipocampo/fisiología , Memoria/fisiología , Núcleos del Rafe/fisiología , Animales , Reacción de Prevención/fisiología , Relojes Biológicos , Región CA1 Hipocampal/fisiología , Condicionamiento Clásico/fisiología , Miedo , Neuronas GABAérgicas/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Optogenética , Estimulación Luminosa , Distribución Aleatoria , Neuronas Serotoninérgicas/fisiología
9.
Biol Psychiatry ; 76(1): 47-56, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24239129

RESUMEN

BACKGROUND: Chronic methamphetamine (METH) exposure causes neuroadaptations at glutamatergic synapses. METHODS: To identify the METH-induced epigenetic underpinnings of these neuroadaptations, we injected increasing METH doses to rats for 2 weeks and measured striatal glutamate receptor expression. We then quantified the effects of METH exposure on histone acetylation. We also measured METH-induced changes in DNA methylation and DNA hydroxymethylation. RESULTS: Chronic METH decreased transcript and protein expression of GluA1 and GluA2 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) and GluN1 N-methyl-D-aspartate receptor subunits. These changes were associated with altered electrophysiological glutamatergic responses in striatal neurons. Chromatin immunoprecipitation-polymerase chain reaction revealed that METH decreased enrichment of acetylated histone H4 on GluA1, GluA2, and GluN1 promoters. Methamphetamine exposure also increased repressor element-1 silencing transcription factor (REST) corepressor 1, methylated CpG binding protein 2, and histone deacetylase 2 enrichment, but not of sirtuin 1 or sirtuin 2, onto GluA1 and GluA2 gene sequences. Moreover, METH caused interactions of REST corepressor 1 and methylated CpG binding protein 2 with histone deacetylase 2 and of REST with histone deacetylase 1. Surprisingly, methylated DNA immunoprecipitation and hydroxymethylated DNA immunoprecipitation-polymerase chain reaction revealed METH-induced decreased enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at GluA1 and GluA2 promoter sequences. Importantly, the histone deacetylase inhibitor, valproic acid, blocked METH-induced decreased expression of AMPAR and N-methyl-D-aspartate receptor subunits. Finally, valproic acid also attenuated METH-induced decrease H4K16Ac recruitment on AMPAR gene sequences. CONCLUSIONS: These observations suggest that histone H4 hypoacetylation may be the main determinant of METH-induced decreased striatal glutamate receptor expression.


Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Metanfetamina/farmacología , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/genética , Acetilación/efectos de los fármacos , Animales , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiología , Metilación de ADN/efectos de los fármacos , Proteínas de Unión al ADN/metabolismo , Histona Desacetilasa 1/antagonistas & inhibidores , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/antagonistas & inhibidores , Histona Desacetilasa 2/metabolismo , Histonas/metabolismo , Masculino , Neuronas/efectos de los fármacos , Neuronas/fisiología , Ratas , Receptores AMPA/biosíntesis , Receptores de N-Metil-D-Aspartato/biosíntesis , Proteínas Represoras/metabolismo , Sirtuina 1/metabolismo , Sirtuina 2/metabolismo , Ácido Valproico/farmacología
10.
Neuron ; 80(2): 507-18, 2013 Oct 16.
Artículo en Inglés | MEDLINE | ID: mdl-24139047

RESUMEN

Imagination, defined as the ability to interpret reality in ways that diverge from past experience, is fundamental to adaptive behavior. This can be seen at a simple level in our capacity to predict novel outcomes in new situations. The ability to anticipate outcomes never before received can also influence learning if those imagined outcomes are not received. The orbitofrontal cortex is a key candidate for where the process of imagining likely outcomes occurs; however, its precise role in generating these estimates and applying them to learning remain open questions. Here we address these questions by showing that single-unit activity in the orbitofrontal cortex reflects novel outcome estimates. The strength of these neural correlates predicted both behavior and learning, learning that was abolished by temporally specific inhibition of orbitofrontal neurons. These results are consistent with the proposal that the orbitofrontal cortex is critical for integrating information to imagine future outcomes.


Asunto(s)
Condicionamiento Clásico/fisiología , Imaginación/fisiología , Corteza Prefrontal/fisiología , Potenciales de Acción/fisiología , Animales , Señales (Psicología) , Extinción Psicológica/fisiología , Masculino , Inhibición Neural/fisiología , Neuronas/fisiología , Ratas
11.
J Neurosci ; 33(24): 9920-31, 2013 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-23761887

RESUMEN

Febrile seizures are associated with increased brain temperature and are often resistant to treatments with antiepileptic drugs, such as carbamazepine and phenytoin, which are sodium channel blockers. Although they are clearly correlated with the hyperthermic condition, the precise cellular mechanisms of febrile seizures remain unclear. We performed patch-clamp recordings from pyramidal cells in acute rat brain slices at temperatures up to 40°C and found that, at ≥37°C, L-type calcium channels are active at unexpectedly hyperpolarized potentials and drive intrinsic firing, which is also supported by a temperature-dependent, gadolinium-sensitive sodium conductance. Pharmacological data, RT-PCR, and the current persistence in Cav1.3 knock-out mice suggested a critical contribution of Cav1.2 subunits to the temperature-dependent intrinsic firing, which was blocked by nimodipine. Because intrinsic firing may play a critical role in febrile seizures, we tested the effect of nimodipine in an in vivo model of febrile seizures and found that this drug dramatically reduces both the incidence and duration of febrile seizures in rat pups, suggesting new possibilities of intervention for this important pathological condition.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Canales de Calcio Tipo L/metabolismo , Hipocampo/patología , Células Piramidales/fisiología , Convulsiones Febriles/patología , Temperatura , Anilidas/farmacología , Animales , Animales Recién Nacidos , Cloruro de Cadmio/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo L/deficiencia , Canales de Calcio Tipo L/genética , Cinamatos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Electroencefalografía , Técnicas In Vitro , Masculino , Ratones , Ratones Noqueados , Nimodipina/farmacología , Técnicas de Placa-Clamp , Ratas , Ratas Long-Evans , Convulsiones Febriles/genética , Convulsiones Febriles/prevención & control
12.
Nature ; 496(7445): 359-62, 2013 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-23552889

RESUMEN

Loss of control over harmful drug seeking is one of the most intractable aspects of addiction, as human substance abusers continue to pursue drugs despite incurring significant negative consequences. Human studies have suggested that deficits in prefrontal cortical function and consequential loss of inhibitory control could be crucial in promoting compulsive drug use. However, it remains unknown whether chronic drug use compromises cortical activity and, equally important, whether this deficit promotes compulsive cocaine seeking. Here we use a rat model of compulsive drug seeking in which cocaine seeking persists in a subgroup of rats despite delivery of noxious foot shocks. We show that prolonged cocaine self-administration decreases ex vivo intrinsic excitability of deep-layer pyramidal neurons in the prelimbic cortex, which was significantly more pronounced in compulsive drug-seeking animals. Furthermore, compensating for hypoactive prelimbic cortex neurons with in vivo optogenetic prelimbic cortex stimulation significantly prevented compulsive cocaine seeking, whereas optogenetic prelimbic cortex inhibition significantly increased compulsive cocaine seeking. Our results show a marked reduction in prelimbic cortex excitability in compulsive cocaine-seeking rats, and that in vivo optogenetic prelimbic cortex stimulation decreased compulsive drug-seeking behaviours. Thus, targeted stimulation of the prefrontal cortex could serve as a promising therapy for treating compulsive drug use.


Asunto(s)
Conducta Adictiva/fisiopatología , Cocaína/farmacología , Corteza Prefrontal/fisiología , Corteza Prefrontal/fisiopatología , Animales , Conducta Adictiva/inducido químicamente , Conducta Adictiva/terapia , Channelrhodopsins , Cocaína/administración & dosificación , Electrochoque , Sistema Límbico/citología , Sistema Límbico/efectos de los fármacos , Sistema Límbico/fisiología , Sistema Límbico/fisiopatología , Masculino , Optogenética , Estimulación Luminosa , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/patología , Células Piramidales/citología , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Ratas , Ratas Wistar , Autoadministración , Estimulación Química
13.
J Neurosci ; 33(1): 214-26, 2013 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-23283335

RESUMEN

Relapse to maladaptive eating habits during dieting is often provoked by stress. Recently, we identified a role of dorsal medial prefrontal cortex (mPFC) neurons in stress-induced reinstatement of palatable food seeking in male rats. It is unknown whether endogenous neural activity in dorsal mPFC drives stress-induced reinstatement in female rats. Here, we used an optogenetic approach, in which female rats received bilateral dorsal mPFC microinjections of viral constructs coding light-sensitive eNpHR3.0-eYFP or control eYFP protein and intracranial fiber optic implants. Rats were food restricted and trained to lever press for palatable food pellets. Subsequently, pellets were removed, and lever pressing was extinguished; then the effect of bilateral dorsal mPFC light delivery on reinstatement of food seeking was assessed after injections of the pharmacological stressor yohimbine (an α-2 andrenoceptor antagonist) or pellet priming, a manipulation known to provoke food seeking in hungry rats. Dorsal mPFC light delivery attenuated yohimbine-induced reinstatement of food seeking in eNpHR3.0-injected but not eYFP-injected rats. This optical manipulation had no effect on pellet-priming-induced reinstatement or ongoing food-reinforced responding. Dorsal mPFC light delivery attenuated yohimbine-induced Fos immunoreactivity and disrupted neural activity during in vivo electrophysiological recording in awake rats. Optical stimulation caused significant outward currents and blocked electrically evoked action potentials in eNpHR3.0-injected but not eYFP-injected mPFC hemispheres. Light delivery alone caused no significant inflammatory response in mPFC. These findings indicate that intracranial light delivery in eNpHR3.0 rats disrupts endogenous dorsal mPFC neural activity that plays a role in stress-induced relapse to food seeking in female rats.


Asunto(s)
Ingestión de Alimentos/fisiología , Extinción Psicológica/efectos de los fármacos , Conducta Alimentaria/fisiología , Corteza Prefrontal/fisiología , Estrés Psicológico/fisiopatología , Animales , Ingestión de Alimentos/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Femenino , Inhibición Psicológica , Optogenética , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Long-Evans , Refuerzo en Psicología , Autoadministración , Yohimbina/farmacología
14.
Pain ; 152(12): 2827-2835, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22033365

RESUMEN

We have proposed that neuropathic pain engages emotional learning, suggesting the involvement of the hippocampus. Because cytokines in the periphery contribute to induction and maintenance of neuropathic pain but might also participate centrally, we used 2 neuropathic pain models, chronic constriction injury (CCI) and spared nerve injury (SNI), to investigate the temporal profile of hippocampal cytokine gene expression in 2 rat strains that show different postinjury behavioral threshold sensitivities. SNI induced long-lasting allodynia in both strains, while CCI induced allodynia with time-dependent recovery in Sprague Dawley (SD) and no allodynia in Wistar Kyoto (WK) rats. In WK rats, only SNI induced sustained upregulation of hippocampal interleukin (IL)-1ß, while IL-6 expression was transiently increased and no significant changes in IL-1ra expression were detected. Conversely, in SD rats, SNI resulted in sustained and robust increased hippocampal IL-1ß expression, which was only transient in rats with CCI. In this strain, IL-6 expression was not affected in any of the 2 injury models and IL-1ra expression was significantly increased in rats with SNI or CCI at late phases. We found that the degree and development of neuropathic pain depend on the specific nerve injury model and rat strain; that hippocampal IL-1ß mRNA levels correlate with neuropathic pain behavior; that, in contrast to sham-operated animals, there are no correlations between hippocampal IL-1ß and IL-1ra or IL-6 in neuropathic rats; and that alterations in cytokine expression are restricted to the hippocampus contralateral to the injury side, again implying that the observed changes reflect nociception.


Asunto(s)
Dolor Crónico/inmunología , Hipocampo/inmunología , Interleucina-1beta/biosíntesis , Neuralgia/inmunología , Animales , Conducta Animal/fisiología , Dolor Crónico/fisiopatología , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/antagonistas & inhibidores , Proteína Antagonista del Receptor de Interleucina 1/genética , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Neuralgia/fisiopatología , Traumatismos de los Nervios Periféricos/inmunología , Traumatismos de los Nervios Periféricos/metabolismo , Ratas , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Especificidad de la Especie
15.
J Physiol ; 588(Pt 20): 3869-82, 2010 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-20724367

RESUMEN

The electrophysiological phenotype of individual neurons critically depends on the biophysical properties of the voltage-gated channels they express. Differences in sodium channel gating are instrumental in determining the different firing phenotypes of pyramidal cells and interneurons; moreover, sodium channel modulation represents an important mechanism of action for many widely used CNS drugs. Flufenamic acid (FFA) is a non-steroidal anti-inflammatory drug that has been long used as a blocker of calcium-dependent cationic conductances. Here we show that FFA inhibits voltage-gated sodium currents in hippocampal pyramidal neurons; this effect is dose-dependent with IC(50) = 189 µm. We used whole-cell and nucleated patch recordings to investigate the mechanisms of FFA modulation of TTX-sensitive voltage-gated sodium current. Our data show that flufenamic acid slows down the inactivation process of the sodium current, while shifting the inactivation curve ~10 mV toward more hyperpolarized potentials. The recovery from inactivation is also affected in a voltage-dependent way, resulting in slower recovery at hyperpolarized potentials. Recordings from acute slices demonstrate that FFA reduces repetitive- and abolishes burst-firing in CA1 pyramidal neurons. A computational model based on our data was employed to better understand the mechanisms of FFA action. Simulation data support the idea that FFA acts via a novel mechanism by reducing the voltage dependence of the sodium channel fast inactivation rates. These effects of FFA suggest that it may be an effective anti-epileptic drug.


Asunto(s)
Potenciales de Acción/efectos de los fármacos , Ácido Flufenámico/farmacología , Activación del Canal Iónico/efectos de los fármacos , Células Piramidales/efectos de los fármacos , Canales de Sodio/fisiología , Potenciales de Acción/fisiología , Animales , Electrofisiología , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Activación del Canal Iónico/fisiología , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Modelos Biológicos , Células Piramidales/fisiología , Ratas , Ratas Long-Evans
16.
Nat Genet ; 42(2): 165-9, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20037587

RESUMEN

Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC, also known as HMSN2C or Charcot-Marie-Tooth disease type 2C (CMT2C)) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. We originally described a large New England family of French-Canadian origin with SPSMA and an American family of English and Scottish descent with CMT2C. We mapped SPSMA and CMT2C risk loci to 12q24.1-q24.31 with an overlapping region between the two diseases. Further analysis reduced the CMT2C risk locus to a 4-Mb region. Here we report that SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4). Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins. Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy for these disorders.


Asunto(s)
Alelos , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/genética , Atrofia Muscular Espinal/complicaciones , Atrofia Muscular Espinal/genética , Mutación/genética , Canales Catiónicos TRPV/genética , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Análisis Mutacional de ADN , Femenino , Humanos , Soluciones Hipotónicas/farmacología , Activación del Canal Iónico/efectos de los fármacos , Masculino , Datos de Secuencia Molecular , Atrofia Muscular Espinal/patología , Atrofia Muscular Espinal/fisiopatología , Proteínas Mutantes/metabolismo , Linaje , Transporte de Proteínas/efectos de los fármacos , Canales Catiónicos TRPV/química , Transfección
17.
Proc Natl Acad Sci U S A ; 106(7): 2423-8, 2009 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-19171885

RESUMEN

Neuropathic pain is a chronic pain that results from lesion or dysfunction of the nervous system. Depression and cognitive decline are often coupled to chronic pain, suggesting the involvement of cortical areas associated with higher cognitive functions. We investigated layer 2/3 pyramidal neurons in acute slices of the contralateral medial prefrontal cortex (mPFC) in the rat spared nerve injury (SNI) model of neuropathic pain and found morphological and functional differences between the mPFC of SNI and sham-operated animals. Basal, but not apical, dendrites of neurons from SNI rats are longer and have more branches than their counterparts in sham-operated animals; spine density is also selectively increased in basal dendrites of neurons from SNI rats; the morphological changes are accompanied by increased contribution to synaptic currents of the NMDA component. Interestingly, the NMDA/AMPA ratio of the synaptic current elicited in mPFC neurons by afferent fiber stimulation shows linear correlation with the rats' tactile threshold in the injured (but not in the contralateral) paw. Our results not only provide evidence that neuropathic pain leads to rearrangement of the mPFC, which may help defining the cellular basis for cognitive impairments associated with chronic pain, but also show pain-associated morphological changes in the cortex at single neuron level.


Asunto(s)
Neuralgia/metabolismo , Manejo del Dolor , Corteza Prefrontal/fisiología , Animales , Conducta Animal/fisiología , Encéfalo/metabolismo , Corteza Cerebral/fisiopatología , Dendritas/metabolismo , Electrofisiología , Neuronas/metabolismo , Neuronas/patología , Umbral del Dolor/fisiología , Técnicas de Placa-Clamp , Corteza Prefrontal/metabolismo , Ratas
18.
Hum Mol Genet ; 18(4): 723-36, 2009 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-19039037

RESUMEN

We herein provide a thorough description of new transgenic mouse models for dentatorubral-pallidoluysian atrophy (DRPLA) harboring a single copy of the full-length human mutant DRPLA gene with 76 and 129 CAG repeats. The Q129 mouse line was unexpectedly obtained by en masse expansion based on the somatic instability of 76 CAG repeats in vivo. The mRNA expression levels of both Q76 and Q129 transgenes were each 80% of that of the endogenous mouse gene, whereas only the Q129 mice exhibited devastating progressive neurological phenotypes similar to those of juvenile-onset DRPLA patients. Electrophysiological studies of the Q129 mice demonstrated age-dependent and region-specific presynaptic dysfunction in the globus pallidus and cerebellum. Progressive shrinkage of distal dendrites of Purkinje cells and decreased currents through alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and gamma-aminobutyrate type A receptors in CA1 neurons were also observed. Neuropathological studies of the Q129 mice revealed progressive brain atrophy, but no obvious neuronal loss, associated with massive neuronal intranuclear accumulation (NIA) of mutant proteins with expanded polyglutamine stretches starting on postnatal day 4, whereas NIA in the Q76 mice appeared later with regional specificity to the vulnerable regions of DRPLA. Expression profile analyses demonstrated age-dependent down-regulation of genes, including those relevant to synaptic functions and CREB-dependent genes. These results suggest that neuronal dysfunction without neuronal death is the essential pathophysiologic process and that the age-dependent NIA is associated with nuclear dysfunction including transcriptional dysregulations. Thus, our Q129 mice should be highly valuable for investigating the mechanisms of disease pathogenesis and therapeutic interventions.


Asunto(s)
Epilepsias Mioclónicas Progresivas/fisiopatología , Proteínas del Tejido Nervioso/genética , Expansión de Repetición de Trinucleótido , Factores de Edad , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Epilepsias Mioclónicas Progresivas/genética , Epilepsias Mioclónicas Progresivas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuronas/metabolismo , Fenotipo , Transmisión Sináptica
19.
J Neurophysiol ; 100(6): 3351-60, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18945818

RESUMEN

Neuronal firing is regulated by the complex interaction of multiple depolarizing and hyperpolarizing currents; intrinsic firing, which defines the neuronal ability to generate action potentials in the absence of synaptic excitation, is particularly sensitive to modulation by currents that are active below the action potential threshold. Cerebellar unipolar brush cells (UBCs) are excitatory granule layer interneurons that are capable of intrinsic firing; here we show that, in acute mouse cerebellar slices, barium-sensitive background potassium channels of UBCs effectively regulate intrinsic firing. We also demonstrate that these channels are regulated by group II metabotropic glutamate receptors (mGluRs), which we show to be present in both of the known subsets of UBCs, one of which expresses calretinin and the other mGluR1alpha. Finally, we show that background potassium currents controlling UBCs' firing are mediated by at least two channel types, one of which is sensitive and the other insensitive to the GIRK blocker tertiapin. Thus in UBCs, glutamatergic transmission appears to have a complex bimodal effect: although it increases spontaneous firing through activation of ionotropic receptors, it also has inhibitory effects through the mGluR-dependent activation of tertiapin-sensitive and -insensitive background potassium currents.


Asunto(s)
Potenciales de Acción/fisiología , Cerebelo/citología , Interneuronas/fisiología , Inhibición Neural/fisiología , Receptores de Glutamato Metabotrópico/fisiología , Potenciales de Acción/efectos de los fármacos , Aminoácidos/farmacología , Animales , Bario/farmacología , Venenos de Abeja/farmacología , Calbindina 2 , Cicloleucina/análogos & derivados , Cicloleucina/farmacología , Agonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Técnicas In Vitro , Interneuronas/clasificación , Interneuronas/efectos de los fármacos , Masculino , Ratones , Inhibición Neural/efectos de los fármacos , Bloqueadores de los Canales de Potasio/farmacología , Receptores de Glutamato Metabotrópico/antagonistas & inhibidores , Receptores de Glutamato Metabotrópico/metabolismo , Proteína G de Unión al Calcio S100/metabolismo , Xantenos/farmacología
20.
Cereb Cortex ; 13(3): 252-64, 2003 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-12571115

RESUMEN

The receptor tyrosine kinases represent an important class of signal transduction molecules that have been shown to play critical roles in neural development. We report in the present study that the neuregulin receptor ErbB4 is preferentially expressed by interneurons that are migrating tangentially from the ventral to the dorsal rat telencephalon. ErbB4 immunoreactivity was detected in the medial ganglionic eminence as early as embryonic day (E) 13 at the inception of tangential migration. Prominent ErbB4-positive migratory streams consisting of cells double-labeled with ErbB4 and Dlx, a marker of tangentially migrating cells, were found to advance along the lower intermediate zone and the marginal zone from the ventrolateral to the dorsomedial cortex at E16-E18. After E20, the ErbB4-positive stream in the lower intermediate zone shifted towards the germinal zone and further extended via the cortex into the hippocampal primordium. ErbB4 was not expressed by Tbr1-positive glutamatergic projection neurons during development. ErbB4 was preferentially expressed by the majority of parvalbumin-positive interneurons and subsets of other GABAergic interneurons in the cerebral cortex and the hippocampus in adulthood. The early onset and preferential expression of ErbB4 in tangentially migrating interneurons suggests that neuregulin/ErbB4 signaling may regulate the development and function of telencephalic interneurons.


Asunto(s)
Movimiento Celular/fisiología , Corteza Cerebral/metabolismo , Receptores ErbB/biosíntesis , Hipocampo/metabolismo , Interneuronas/metabolismo , Neurregulinas/fisiología , Animales , Corteza Cerebral/citología , Corteza Cerebral/embriología , Corteza Cerebral/crecimiento & desarrollo , Femenino , Regulación del Desarrollo de la Expresión Génica/fisiología , Hipocampo/citología , Hipocampo/embriología , Hipocampo/crecimiento & desarrollo , Interneuronas/citología , Neurregulinas/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Receptor ErbB-4
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