RESUMEN
Dopamine D3 receptors (D3Rs) are implicated in several aspects of cognition, but their role in aversive conditioning has only been marginally uncovered. Investigations have reported that blockade of D3Rs enhances the acquisition of fear memories, a phenomenon tightly linked to the neuropeptide pituitary adenylate cyclase-activating peptide (PACAP). However, the impact of D3R ablation on the PACAPergic system in regions critical for the formation of new memories remains unexplored. To address this issue, levels of PACAP and its receptors were compared in the hippocampus and cerebral cortex (CX) of mice devoid of functional D3Rs (D3R(-/-)) and wild-types (WTs) using a series of comparative immunohistochemical and biochemical analyses. Morphometric and stereological data revealed increased hippocampal area and volume in D3R(-/-) mice, and augmented neuronal density in CA1 and CA2/3 subfields. PACAP levels were increased in the hippocampus of D3R(-/-) mice. Expression of PACAP receptors was also heightened in mutant mice. In the CX, PACAP immunoreactivity (IR), was restricted to cortical layer V in WTs, but was distributed throughout layers IV-VI in D3R(-/-) mice, along with increased mRNAs, protein concentration and staining scores. Consistently, PAC1, VPAC1 and VPAC2 IRs were variably redistributed in CX, with a general upregulation in cortical layers II-IV in knockout animals. Our interpretation of these findings is that disturbed dopamine neurotransmission due to genetic D3R blockade may enhance the PACAP/PAC1-VPAC axis, a key endogenous system for the processing of fear memories. This could explain, at least in part, the facilitated acquisition and consolidation of aversive memories in D3R(-/-) mice.
Asunto(s)
Corteza Cerebral/metabolismo , Regulación de la Expresión Génica/genética , Hipocampo/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/metabolismo , Receptores de Dopamina D3/deficiencia , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Análisis de Varianza , Animales , Corteza Cerebral/anatomía & histología , Hipocampo/anatomía & histología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuroimagen , Neuronas/metabolismo , Receptores de Dopamina D3/genética , Receptores de Tipo II del Péptido Intestinal Vasoactivo/metabolismo , Receptores de Tipo I del Polipéptido Intestinal Vasoactivo/metabolismoRESUMEN
The co-morbidity of mood disturbance, in a proportion of patients, is now described across a wide range of chronic disease states. Similarly, a 'Low Thyroid Syndrome' is also reported in a proportion of individuals with chronic diseases. Here, we report on central changes in an animal model of inflammatory stress in which altered social behaviour, representing social disability, persists in a sub-group of rats following injury. We showed in an earlier study that rats with social disability following injury have significantly decreased peripheral thyroid hormones, with no increase in Thyroid Stimulating Hormone (TSH). Only rats identified by behavioural change showed changes in hypothalamic gene expression. In whole hypothalamus extracted RNA, relative expression of mRNA for Thyrotrophin-releasing hormone (TRH) was significantly down-regulated in disabled rats (p=0.039) and deiodinase 3 up-regulated (p=0.006) compared to controls. Specifically in the paraventricular nucleus (PVN), numbers of immunoreactive cells for deiodinase 3-like and thyroid hormone receptor beta-like proteins were decreased in the sub-group with disability compared to the control group (p=0.031 and p=0.011 respectively). In rats with behavioural change post-injury, down-regulation of TRH provides an explanation for the failure of the hypothalamo-pituitary-thyroid (HPT) axis to respond to the post-injury decrease in thyroxine. Decreased local expression of deiodinase 3 protein, resulting in a local increase in T3, offers an explanation for down regulation of TRH in the hypophysiotrophic TRH neurons. It is possible that, in a sub-group of animals identified behaviourally, a mechanism resulting in hypothalamic down-regulation of the HPT axis persists following inflammatory injury.
Asunto(s)
Hipotálamo/metabolismo , Nervio Ciático/lesiones , Nervio Ciático/metabolismo , Conducta Social , Glándula Tiroides/metabolismo , Animales , Inflamación/metabolismo , Yoduro Peroxidasa/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Estrés Fisiológico , Receptores beta de Hormona Tiroidea/metabolismo , Tirotropina/metabolismo , Yodotironina Deyodinasa Tipo IIRESUMEN
Following unilateral chronic constriction injury (CCI) of the sciatic nerve, histochemical and gene expression changes were examined in the rat nucleus accumbens (NAcc), a region critical to affective-motivational regulation. Rats were categorised as having Pain alone (45%) or Pain and Disability (30%), on the basis of either unaltered or decreased dominance behaviour in the resident-intruder paradigm, respectively. Tyrosine hydroxylase (TH) expression was significantly increased bilaterally, throughout the rostrocaudal extent of the NAcc in Pain alone animals. Increased TH likely reflects increased dopamine levels in the Pain alone group, which may modulate dopamine receptor subtype 2 (D2) receptor expression. Stereological analyses of D2 receptor immunoreactive (D2-IR) cells revealed lateralised changes which correlated significantly with dominance behaviour. In the contralateral NAcc, D2-IR negatively correlated with post-CCI dominance behaviour (i.e. Pain alone animals have decreased D2-IR), whereas ipsilaterally there was a positive correlation between D2-IR and post-CCI dominance behaviour (i.e. Pain and Disability animals have decreased D2-IR). Western blots for D2 protein expression confirmed these correlations. Additionally, D2 mRNA expression within the NAcc showed lateralised and group specific changes. In the ipsilateral NAcc D2 mRNA was increased in Pain alone animals. It is hypothesised that increased D2 mRNA in the ipsilateral NAcc of Pain alone animals may be a protective mechanism, maintaining D2-IR despite increased dopamine, which may otherwise induce receptor desensitisation. D2 mRNA is not altered in the ipsilateral NAcc of Pain and Disability animals, therefore loss of D2-IR is likely, albeit by an alternate mechanism. In summary, unilateral CCI in rats induces specific and lateralised adaptations in the dopaminergic circuitry of the NAcc. These distinct neural adaptations correlate with changes in social behaviour, and likely underlie some of the affective-motivational state changes associated with neuropathic pain in a subset of rats (i.e. Pain and Disability group).
Asunto(s)
Dopamina/metabolismo , Regulación de la Expresión Génica/fisiología , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Neuropatía Ciática/patología , Análisis de Varianza , Animales , Calbindinas , Evaluación de la Discapacidad , Modelos Animales de Enfermedad , Dopamina/genética , Lateralidad Funcional , Hiperalgesia/etiología , Modelos Lineales , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/genética , Receptores de Dopamina D3/genética , Proteína G de Unión al Calcio S100/metabolismo , Neuropatía Ciática/complicaciones , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Hypothyroidism is associated with a disturbance of behaviour and mood. There are also individuals, not classified as hypothyroid, with low to 'low normal' thyroid hormone levels and normal thyroid-stimulating hormone (TSH) levels who have mood and behavioural changes. As the peripheral thyroid hormones decrease, TSH is expected to increase. However, there are a number of physiological mechanisms known to suppress TSH. In the present study, we report on thyroid hormone regulation in a rat model of neuropathic pain and altered social behaviour that is usually transient, but is persistent in a sub-group of the population. Following ligation of the sciatic nerve, male Sprague-Dawley rats were assessed for social dominance towards an intruder: 20% showed persistently decreased social dominance. Plasma levels of thyroid hormones, TSH and corticosterone were measured before and on days 2, 3, 4, 5 and 6 after injury in 21 rats. The mean plasma thyroxine (T4), free thyroxine (fT4) and triiodothyronine (T3) levels decreased significantly post-injury in rats with persistently changed behaviour compared to rats with unchanged behaviour (P < or = 0.002). There was no significant difference between groups for mean change in free triiodothyronine (fT3) or TSH. There was a correlation between decreased dominance behaviour and decrease in both T4 (r = 0.62, P = 0.009) and fT4 (r = 0.71, P = 0.001), but no correlation with TSH. In a sub-population of rats, decreased thyroid hormones did not result in the expected increased levels of TSH to restore pre-injury levels, nor did they show increased hypothalamic thyrotrophin-releasing hormone mRNA expression, indicating altered hypothalamic-pituitary-thyroid axis regulation. Because T3 availability to the brain is dependent on both circulating T3 and T4, decreased peripheral thyroid hormones may result in changed neural function, as expressed in altered complex behaviours in this sub-population of rats.
Asunto(s)
Conducta Animal/fisiología , Hipotiroidismo/fisiopatología , Neuralgia/sangre , Nervio Ciático/lesiones , Hormonas Tiroideas/sangre , Animales , Constricción , Corticosterona/sangre , Humanos , Hipotálamo/metabolismo , Masculino , Neuralgia/etiología , Neuralgia/fisiopatología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Conducta Social , Hormonas Tiroideas/genética , Hormona Liberadora de Tirotropina/sangre , Hormona Liberadora de Tirotropina/genéticaRESUMEN
Neuropathic pain conditions for which treatment is sought are characterized by complex behavioural disturbances, as well as "pain." Recent studies using chronic constriction injury of the sciatic nerve have shown that rats develop three distinct patterns of disability characterized by changes in social-interactions and sleep-wake cycle behaviours post-injury: (i) Persistent Disability, (ii) Transient Disability and (iii) No Disability. These patterns occur despite all rats showing identical levels of allodynia and hyperalgesia (i.e., pain). In rats, social-interactions and sleep-wake cycle behaviours are regulated in part, by neural networks, which converge on the periaqueductal grey (PAG). We sought therefore to identify neural adaptations in the PAG, 6 days following chronic constriction injury (CCI), the time at which rats in which disabilities persist are first distinguished from those without disabilities (i.e., No Disability and Transient Disability). GeneChips, RT-PCR and Western blotting revealed the select up-regulation in translation and transcription of glial fibrillary acidic protein (GFAP) and Vimentin in rats with Persistent Disability. Significant increases in GFAP immunoreactivity were localized histologically to the lateral and caudal ventrolateral columns of the PAG. This anatomically specific pattern of increased GFAP suggests activation of astrocytes by select neural pathways, which likely include afferents of both spinal and nucleus of the solitary tract (NTS) origin. The PAG columns in which astrocytes are activated play significant roles in modulating both social-interactions and the sleep-wake cycle. It is possible therefore that the persistent disabilities seen in a subgroup of CCI rats are in part a functional consequence of this specific pattern of astrocyte activation.
Asunto(s)
Gliosis/fisiopatología , Neuralgia/fisiopatología , Neuroglía/metabolismo , Sustancia Gris Periacueductal/fisiopatología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Neuropatía Ciática/fisiopatología , Animales , Conducta Animal/fisiología , Biomarcadores/análisis , Biomarcadores/metabolismo , Western Blotting , Evaluación de la Discapacidad , Modelos Animales de Enfermedad , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Gliosis/etiología , Gliosis/patología , Inmunohistoquímica , Masculino , Trastornos del Humor/etiología , Trastornos del Humor/patología , Trastornos del Humor/fisiopatología , Neuralgia/patología , Neuroglía/citología , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/patología , Enfermedades del Sistema Nervioso Periférico/patología , Ratas , Ratas Sprague-Dawley , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Neuropatía Ciática/patología , Sueño/fisiología , Trastornos del Sueño-Vigilia/etiología , Trastornos del Sueño-Vigilia/patología , Trastornos del Sueño-Vigilia/fisiopatología , Conducta Social , Regulación hacia Arriba/fisiología , Vimentina/genética , Vimentina/metabolismoRESUMEN
Previous research has suggested that the ventrolateral column of the periaqueductal gray (vlPAG) plays a crucial role in triggering a decompensatory response (sympathoinhibition, hypotension, bradycardia) to severe blood loss. vlPAG excitation triggers also quiescence, decreased vigilance and decreased reactivity, the behavioral response which usually accompanies hypovolemic shock. The aim of this study was to identify, in unanesthetized rats, the main descending pathway(s) via which vlPAG neurons trigger sympathoinhibition and bradycardia in response to severe blood loss. Firstly, immediate early gene (c-Fos) expression was used to identify vlPAG neurons selectively activated by severe blood loss. Subsequently, the specific medullary projections of these vlPAG neurons were defined by combined c-Fos, retrograde tracing (double-label) experiments. It was found that vlPAG neurons selectively activated by severe hemorrhage project overwhelmingly to the vasodepressor portion of the caudal midline medulla (CMM). Previous studies indicate that this CMM region mediates behaviorally-coupled cardiovascular adjustments and the findings described here fit with the idea that CMM neurons are uniquely recruited by salient challenges, the adaptive responses to which require more than reflexive homeostatic cardiovascular adjustments.
Asunto(s)
Bulbo Raquídeo/fisiología , Sustancia Gris Periacueductal/fisiología , Choque/patología , Vías Aferentes/fisiología , Amidinas/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Mapeo Encefálico , Regulación de la Expresión Génica/fisiología , Hemorragia/patología , Masculino , Neuronas/metabolismo , Nitroprusiato/farmacología , Proteínas Oncogénicas v-fos/metabolismo , Sustancia Gris Periacueductal/patología , Ratas , Ratas Sprague-Dawley , Estilbamidinas/metabolismo , Vasodilatadores/farmacologíaRESUMEN
Previous studies using c-Fos immunohistochemistry suggest that a sub-population of neurons in the midbrain periaqueductal gray region is activated during opioid withdrawal. The neurochemical identity of these cells is unknown but cellular physiological studies have implicated GABAergic neurons. The present study investigated whether GABAergic neurons are activated in the mouse periaqueductal gray during opioid withdrawal using dual-antibody immunohistochemistry for Fos and glutamic acid decarboxylase. Both chronic opioid treatment and naloxone-precipitated opioid withdrawal increased Fos expression in the periaqueductal gray, with the greatest increase being four-fold in the caudal ventrolateral subdivision following withdrawal. Neurons stained for both Fos and glutamic acid decarboxylase were greatly enhanced in all subdivisions of the periaqueductal gray following withdrawal, particularly in the lateral and ventrolateral divisions where the increase was up to 70-fold. These results suggest that activation of a subpopulation of GABAergic interneurons in the periaqueductal gray plays a role in opioid withdrawal.
Asunto(s)
Genes fos , Glutamato Descarboxilasa/metabolismo , Narcóticos/toxicidad , Neuronas/fisiología , Sustancia Gris Periacueductal/fisiopatología , Síndrome de Abstinencia a Sustancias/fisiopatología , Animales , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Ratones , Naloxona/farmacología , Neuronas/enzimologíaRESUMEN
The haemodynamic response to a fixed volume haemorrhage passes through three distinct phases: a normotensive, compensatory phase; a hypotensive, decompensatory phase; and a post-haemorrhage, recompensatory phase. The role of the forebrain and midbrain in regulating the triphasic response to a 'fast' (1.5%/min) or 'slow' (0.75%/min) rate of blood withdrawal (30% haemorrhage) was evaluated by comparing, in unanaesthetised rats, the effects of pre-collicular (PCD) vs. pre-trigeminal decerebrations (PTD). It was found that pre-trigeminal decerebration attenuated the decompensatory (hypotensive) phase to either a fast or slow haemorrhage. In contrast, pre-collicular decerebration attenuated the compensatory and recompensatory phases of the response to a 'fast' (but not a slow) haemorrhage. These results suggest that the integrity of (i) forebrain structure(s) are critical for compensatory and recompensatory responses to 'rapid' blood loss; and (ii) midbrain structure(s) are critical for the decompensatory response to progressive blood loss irrespective of rate.
Asunto(s)
Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Hemorragia/fisiopatología , Mesencéfalo/fisiología , Prosencéfalo/fisiología , Animales , Hemodinámica/fisiología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The consequences of a severe traumatic injury--deep pain and haemorrhage--usually evoke a passive emotional coping reaction characterised by: quiescence and immobility, decreased vigilance, hypotension and bradycardia. Results of studies utilising microinjections of excitatory amino acids suggest that passive coping reactions are mediated, at least in part, by activation of the midbrain, ventrolateral periaqueductal gray (vlPAG) region. Further, experiments in anaesthetised rats, using the expression of the immediate-early gene, c-fos, as a marker of neuronal activation, report that pain arising from muscles, joints or viscera selectively activates the vlPAG. Anaesthesia alone, however, evokes substantial Fos-like immunoreactivity (IR) within the vlPAG and this may have obscured any differences in patterns of Fos expression following noxious deep somatic versus noxious visceral activation. In these experiments, in unanaesthetised rats, the effects of noxious spinal versus noxious vagal primary afferent activation were re-examined and distinct rostrocaudal patterns of Fos-expression were observed. Specifically: (i) injection of algesic substances into muscle, which preferentially activates spinal afferents, evoked Fos expression predominantly within the caudal vlPAG; whereas, (ii) noxious manipulations whose effects are mediated by (cardiopulmonary) vagal activation evoked preferential Fos-expression within the rostral vlPAG. On the other hand, hypotensive haemorrhage evoked substantial Fos expression along the entire rostrocaudal extent of the vlPAG, a finding which fits with suggestions that haemorrhagic shock is triggered by a combination of: (i) spinally-relayed nociceptive signals originating from ischaemic tissue, and (ii) vagally-relayed signals reflecting poor cardiac filling.
Asunto(s)
Vías Aferentes/fisiología , Sustancia Gris Periacueductal/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Médula Espinal/fisiología , Nervio Vago/fisiología , Analgésicos/farmacología , Animales , Biguanidas/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Dióxido de Carbono/farmacología , Carragenina/farmacología , Recuento de Células , Formaldehído/farmacología , Genes Inmediatos-Precoces/fisiología , Hemorragia/fisiopatología , Hipotensión/fisiopatología , Inyecciones Intramusculares , Masculino , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/inervación , Dimensión del Dolor/efectos de los fármacos , Sustancia Gris Periacueductal/anatomía & histología , Ratas , Ratas Sprague-Dawley , Estimulación Química , Vigilia/efectos de los fármacos , Vigilia/fisiologíaRESUMEN
Previous research using microinjections of excitatory amino acids suggested that the caudal midline medulla (including nucleus raphe obscurus and nucleus raphe pallidus) contained a mixed population of sympathoexcitatory and sympathoinhibitory neurones. The results of this study indicate that different anaesthetic regimes (urethane versus halothane) determine whether sympathoexcitatory (urethane only) or sympathoinhibitory (halothane only) responses are evoked by stimulation within distinct caudal midline medullary regions. In addition, anaesthetic regimes also affect the caudal midline medullary-mediated response to haemorrhage. Specifically, under conditions of urethane anaesthesia, inactivation (lignocaine) of the midline medullary region immediately caudal to the obex, prematurely triggered and dramatically potentiated the hypotension and bradycardia evoked by 15% haemorrhage; whereas under halothane anaesthesia, inactivation of the same region had no effect. In contrast, under urethane anaesthesia, inactivation of the midline medullary region immediately rostral to the obex, delayed the onset of the hypotension and bradycardia to 15% haemorrhage; inactivation of the same region under halothane anaesthesia blocked haemorrhage-evoked hypotension and bradycardia. Our findings indicate that topographically distinct parts of the caudal midline medulla contain neurones (i) that differentially regulate the timing and magnitude of the compensatory (normotensive) versus decompensatory (hypotensive) phases of the response to haemorrhage; and (ii) whose activity is altered by urethane versus halothane anaesthesia.
Asunto(s)
Anestésicos Intravenosos/farmacología , Presión Sanguínea/efectos de los fármacos , Aminoácidos Excitadores/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Hemorragia/fisiopatología , Bulbo Raquídeo/efectos de los fármacos , Bulbo Raquídeo/fisiopatología , Uretano/farmacología , Anestésicos por Inhalación/farmacología , Anestésicos Locales/farmacología , Animales , Halotano/farmacología , Hipotensión/fisiopatología , Lidocaína/farmacología , Masculino , Microinyecciones , Presorreceptores/efectos de los fármacos , Núcleos del Rafe/fisiopatología , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/efectos de los fármacosRESUMEN
Previous work suggested that pain of distinct tissue origins was differentially represented in the midbrain periaqueductal gray (PAG). That is, persistent pain of deep origin (muscle, joint viscera) "activated" ventrolateral PAG neurons and triggered quiescence, hyporeactivity and vasodepression (i.e. passive emotional coping); whereas intermittent cutaneous pain "activated" lateral PAG neurons and triggered fight-flight (i.e. active emotional coping). Cutaneous noxious stimuli, if inescapable however, trigger a passive emotional coping reaction similar to that evoked by pain of deep origin. This raised the question--is it the behavioural significance (escapability versus inescapability) or the tissue origin (cutaneous versus deep) of the pain, that is represented in the PAG? In this study we used immediate-early-gene (c-Fos) expression to examine PAG and spinal activation patterns following "inescapable" (persistent) pain of cutaneous versus deep origin. It was found that selective activation of the ventrolateral PAG and passive emotional coping were evoked by an inescapable cutaneous noxious stimulus (i.e. clip of the neck), as well as by a deep noxious stimulus (i.e. neck muscle pain). In the upper cervical spinal cord, however, these noxious manipulations evoked distinct patterns of Fos expression which reflected the different patterns of primary afferent termination arising from skin versus muscle. The results suggest that whereas pain representation in the spinal cord accurately reflects tissue origin, pain representation in the PAG better reflects behavioural significance.
Asunto(s)
Dolor/fisiopatología , Sustancia Gris Periacueductal/fisiología , Médula Espinal/fisiología , Animales , Conducta Animal/fisiología , Vértebras Cervicales , Emociones/fisiología , Reacción de Fuga , Genes Inmediatos-Precoces/fisiología , Masculino , Actividad Motora , Músculos del Cuello , Dimensión del Dolor , Proteínas Proto-Oncogénicas c-fos/análisis , Ratas , Ratas Wistar , Instrumentos QuirúrgicosRESUMEN
A previous study in the rat revealed that distinct orbital and medial prefrontal cortical (OMPFC) areas projected to specific columns of the midbrain periaqueductal gray region (PAG). This study used anterograde tracing techniques to define projections to the hypothalamus arising from the same OMPFC regions. In addition, injections of anterograde and retrograde tracers were made into different PAG columns to examine connections between hypothalamic regions and PAG columns projected upon by the same OMPFC regions. The most extensive patterns of hypothalamic termination were seen after injection of anterograde tracer in prelimbic and infralimbic (PL/IL) and the ventral and medial orbital (VO/MO) cortices. Projections from rostral PL/IL and VO/MO targeted the rostrocaudal extent of the lateral hypothalamus, as well as lateral perifornical, and dorsal and posterior hypothalamic areas. Projections arising from caudal PL/IL terminated within the dorsal hypothalamus, including the dorsomedial nucleus and dorsal and posterior hypothalamic areas. There were also projections to medial perifornical and lateral hypothalamic areas. In contrast, it was found that anterior cingulate (AC), dorsolateral orbital (DLO), and agranular insular (AId) cortices projected to distinct and restricted hypothalamic regions. Projections arising from AC terminated within dorsal and posterior hypothalamic areas, whereas DLO and AId projected to the lateral hypothalamus. The same OMPFC regions also projected indirectly, by means of specific PAG columns, to many of the same hypothalamic fields. In the context of our previous findings, these data indicate that, in both rat and macaque, parallel but distinct circuits interconnect OMPFC areas with specific hypothalamic regions, as well as PAG columns.
Asunto(s)
Hipotálamo/fisiología , Corteza Prefrontal/fisiología , Ratas/fisiología , Transmisión Sináptica/fisiología , Animales , Mapeo Encefálico , Masculino , Órbita , Ratas Sprague-DawleyRESUMEN
All animals, including humans, react with distinct emotional coping strategies to different types of stress. Active coping strategies (e.g. confrontation, fight, escape) are evoked if the stressor is controllable or escapable. Passive coping strategies (e.g. quiescence, immobility, decreased responsiveness to the environment) are usually elicited if the stressor is inescapable and help to facilitate recovery and healing. Neural substrates mediating active versus passive emotional coping have been identified within distinct, longitudinal neuronal columns of the midbrain periaqueductal gray (PAG) region. Active coping is evoked by activation of either the dorsolateral or lateral columns of the PAG; whereas passive coping is triggered by activation of the ventrolateral PAG. Recent anatomical studies indicate that each PAG column receives a distinctive set of ascending (spinal and medullary) and descending (prefrontal cortical and hypothalamic) afferents. Consistent with the anatomy, functional studies using immediate early gene expression (c-fos) as a marker of neuronal activation have revealed that the preferential activation of a specific PAG column reflects (i) the type of emotional coping reaction triggered, and (ii) whether a physical or psychological stressor was used.
Asunto(s)
Adaptación Psicológica/fisiología , Emociones/fisiología , Red Nerviosa/fisiología , Estrés Psicológico/fisiopatología , Animales , HumanosRESUMEN
Animals, including humans, react with distinct emotional coping strategies to different sets of environmental demands. These strategies include the capacity to affect appropriate responses to "escapable" or "inescapable" stressors. Active emotional coping strategies--fight or flight--are particularly adaptive if the stress is escapable. On the other hand, passive emotional coping strategies-quiescence, immobility, decreased responsiveness to the environment-are useful when the stress is inescapable. Passive strategies contribute also to facilitating recovery and healing once the stressful event is over. Active vs. passive emotional coping strategies are characterised further by distinct patterns of autonomic change. Active strategies are associated with sympathoexcitation (hypertension, tachycardia), whereas passive strategies are associated with sympathoinhibitory patterns (hypotension, bradycardia). Distinct neural substrates mediating active vs. passive emotional coping have been identified within the longitudinal neuronal columns of the midbrain periaqueductal gray region (PAG). The PAG offers then a potentially useful point of entry for delineating neural circuits mediating the different forms of emotional coping and their associated patterns of autonomic activity. As one example, recent studies of the connections of orbital and medial prefrontal cortical (PFC) fields with specific PAG longitudinal neuronal columns are reviewed. Findings of discrete orbital and medial PFC projections to different PAG columns, and related PFC and PAG columnar connections with specific subregions of the hypothalamus, suggest that distinct but parallel circuits mediate the behavioural strategies and patterns of autonomic activity characteristic of emotional "engagement with" or "disengagement from" the external environment.
Asunto(s)
Adaptación Psicológica/fisiología , Sistema Nervioso Autónomo/fisiología , Emociones/fisiología , Vías Nerviosas/fisiología , Estrés Psicológico/fisiopatología , Animales , Sistema Nervioso Autónomo/citología , Fenómenos Fisiológicos Cardiovasculares , Humanos , Bulbo Raquídeo/citología , Bulbo Raquídeo/fisiología , Vías Nerviosas/citología , Sustancia Gris Periacueductal/citología , Sustancia Gris Periacueductal/fisiología , Corteza Prefrontal/citología , Corteza Prefrontal/fisiología , Médula Espinal/citología , Médula Espinal/fisiología , Estrés Psicológico/psicología , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/fisiologíaRESUMEN
Studies utilizing the expression of Fos protein as a marker of neuronal activation have revealed that pain of deep somatic or visceral origin selectively activates the ventrolateral periaqueductal gray (vlPAG). Previous anatomical tracing studies revealed that spinal afferents to the vlPAG arose from the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus at all spinal segmental levels, with approximately 50% of vlPAG-projecting spinal neurons found within the upper cervical spinal cord. This study utilized detection of Fos protein to determine the specific populations of vlPAG-projecting spinal neurons activated by noxious deep somatic or noxious visceral stimulation. Pain of cardiac or peritoneal (i.e., visceral) origin activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the thoracic cord, whereas pain of hindlimb (i.e., deep somatic) origin activated neurons in the same laminar regions but in the lumbosacral cord. Each of these deep noxious manipulations also activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the upper cervical spinal cord. In a second set of experiments, the combination of retrograde tracing and Fos immunohistochemistry revealed that vlPAG-projecting spinal neurons activated by deep somatic pain were located in both the upper cervical and lumbosacral cord, whereas those activated by visceral pain were restricted to the thoracic spinal cord. Thus pain arising from visceral versus deep somatic body regions influences neural activity within the vlPAG via distinct spinal pathways. The findings also highlight the potential significance of the upper cervical cord in integrating pain arising from deep structures throughout the body.
Asunto(s)
Vías Aferentes/fisiopatología , Dolor/fisiopatología , Ratas/fisiología , Médula Espinal/fisiopatología , Vísceras/inervación , Animales , Corazón/fisiopatología , Pulmón/fisiopatología , Masculino , Músculos/fisiopatología , Nociceptores/fisiopatología , Sustancia Gris Periacueductal/fisiopatología , Peritoneo/fisiopatología , Ratas Sprague-Dawley , Médula Espinal/patologíaRESUMEN
Activation of the ventrolateral periaqueductal gray (vlPAG) evokes a reaction of quiescence, immobility, hypotension and bradycardia. Pain of deep somatic or visceral origin also often triggers a reaction of quiescence, immobility, hypotension and bradycardia and further, evokes a selective increase in immediate-early-gene (c-Fos) expression within the vlPAG. Vasodepression evoked from the vlPAG is thought to be mediated by an inhibition of presympathetic neurons within the rostral ventrolateral medulla (RVLM). In this study the prior injection of retrograde tracer into the RVLM was combined with the use of Fos expression as a marker of neuronal activation, to determine if deep (muscle) pain-evoked vasodepression could be mediated by a direct vlPAG-RVLM pathway. It was revealed that intramuscular injection of formalin, in the anaesthetised rat, evoked a significant increase in Fos expression within the caudal vlPAG, and that approximately 25% of the Fos-immunoreactive neurons projected to the RVLM.
Asunto(s)
Bulbo Raquídeo/fisiopatología , Músculos/inervación , Músculos/fisiopatología , Vías Nerviosas/fisiopatología , Dolor/fisiopatología , Sustancia Gris Periacueductal/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Animales , Masculino , Bulbo Raquídeo/patología , Músculos/patología , Vías Nerviosas/patología , Neuronas/metabolismo , Neuronas/patología , Nociceptores/patología , Nociceptores/fisiopatología , Dolor/patología , Sustancia Gris Periacueductal/patología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley , Sistema Nervioso Simpático/patologíaRESUMEN
Within the caudal medulla there are two regions whose activation leads to vasodepression and bradycardia, the caudal ventrolateral medulla and a discrete region of the caudal midline medulla. This study investigated, in the halothane anaesthetized rat, the contribution of these two vasodepressor regions to "homeostatic" and "behaviourally-coupled" cardiovascular regulation. In an initial set of experiments the contribution of each of these two regions to the hypotension and bradycardia evoked by acute hypovolaemia (15% haemorrhage) was investigated. It was found that inactivation of the caudal midline medulla significantly attenuated (cobalt chloride) or completely blunted (lignocaine) the hypotension and bradycardia evoked by acute hypovolaemia. In contrast, inactivation of the caudal ventrolateral medulla using cobalt chloride, although attenuating the magnitude of the hypotension and completely blocking the bradycardia, did not delay the onset of the hypotension evoked by acute hypovolaemia. The caudal ventrolateral medulla is known to be critical in homeostatic cardiovascular control through the expression of the "baroreceptor reflex" and the hypotension and bradycardia evoked by activation of cardiopulmonary afferents. In a second series of experiments we found inactivation of the caudal midline medulla played no role in baroreflex-evoked bradycardia (i.v. phenylephrine) or the hypotension and bradycardia evoked by cardiopulmonary afferent activation (i.v. 5-hydroxytryptamine). These data suggest that the caudal midline medulla and caudal ventrolateral medulla play different roles in cardiovascular control. The caudal ventrolateral medulla is involved in mediating cardiovascular changes associated with a variety of stimuli including "homeostatic" and "behaviourally-coupled" cardiovascular changes, whereas the caudal midline medulla is critical for mediating "behaviourally-coupled" changes in arterial pressure and heart rate.
Asunto(s)
Bradicardia/fisiopatología , Hemorragia/fisiopatología , Hipotensión/fisiopatología , Bulbo Raquídeo/fisiología , Presorreceptores/fisiología , Animales , Antimutagênicos/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Bradicardia/inducido químicamente , Cobalto/farmacología , Depuradores de Radicales Libres/farmacología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Hipotensión/inducido químicamente , Masculino , Bulbo Raquídeo/anatomía & histología , Bulbo Raquídeo/efectos de los fármacos , Modelos Biológicos , Presorreceptores/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Serotonina/farmacología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
We utilised retrograde and anterograde tracing procedures to study the origin and termination of prefrontal cortical (PFC) projections to the periaqueductal gray (PAG) in the rat. A previous study, in the primate, had demonstrated that distinct subgroups of PFC areas project to specific PAG columns. Retrograde tracing experiments revealed that projections to dorsolateral (dlPAG) and ventrolateral (vlPAG) periaqueductal gray columns arose from medial PFC, specifically prelimbic, infralimbic, and anterior cingulate cortices. Injections made in the vlPAG also labeled cells in medial, ventral, and dorsolateral orbital cortex and dorsal and posterior agranular insular cortex. Other orbital and insular regions, including lateral and ventrolateral orbital, ventral agranular insular, and dysgranular and granular insular cortex did not give rise to appreciable projections to the PAG. Anterograde tracing experiments revealed that the projections to different PAG columns arose from specific PFC areas. Projections from the caudodorsal medial PFC (caudal prelimbic and anterior cingulate cortices) terminated predominantly in dlPAG, whereas projections from the rostroventral medial PFC (rostral prelimbic cortex) innervated predominantly the vlPAG. As well, consistent with the retrograde data, projections arising from select orbital and agranular insular cortical areas terminated selectively in the vlPAG. The results indicate: (1) that rat orbital and medial PFC possesses an organisation broadly similar to that of the primate; and (2) that subdivisions within the rat orbital and medial PFC can be recognised on the basis of projections to distinct PAG columns.