Portion Of Medial Prefrontal Cortex Research Articles

The medial prefrontal cortex and the cardiac baroreflex activity: physiological and pathological implications.

The cardiac baroreflex is an autonomic neural mechanism involved in the modulation of the cardiovascular system. It influences the heart rate and peripheral vascular resistance to preserve arterial blood pressure within a narrow variation range. This mechanism is mainly controlled by medullary nuclei located in the brain stem. However, supramedullary areas, such as the ventral portion of medial prefrontal cortex (vMPFC), are also involved. Particularly, the glutamatergic NMDA/NO pathway in the vMPFC can facilitate baroreflex bradycardic and tachycardic responses. In addition, cannabinoid receptors in this same area can reduce or increase those cardiac responses, possibly through alteration in glutamate release. This vMPFC network has been associated to cardiovascular responses during stressful situations. Recent results showed an involvement of glutamatergic, nitrergic, and endocannabinoid systems in the blood pressure and heart rate increases in animals after aversive conditioning. Consequently, baroreflex could be modified by the vMPFC neurotransmission during stressful situations, allowing necessary cardiovascular adjustments. Remarkably, some mental, neurological and neurodegenerative disorders can involve damage in the vMPFC, such as posttraumatic stress disorder, major depressive disorder, Alzheimer's disease, and neuropathic pain. These pathologies are also associated with alterations in glutamate/NO release and endocannabinoid functions along with baroreflex impairment. Thus, the vMPFC seems to play a crucial role on the baroreflex control, either during pathological or physiological stress-related responses. The study of baroreflex mechanism under such pathological view may be helpful to establish causality mechanisms for the autonomic and cardiovascular imbalance found in those conditions. It can explain in the future the reasons of the high cardiovascular risk some neurological and neurodegenerative disease patients undergo. Additionally, the present work offers insights on the possible contributions of vMPFC dysfunction on baroreflex alterations, which, in turn, may raise questions in what extent other brain areas may play a role in autonomic deregulation under such pathological situations.

Effects of a single bilateral infusion of R-ketamine in the rat brain regions of a learned helplessness model of depression

Effects of a single bilateral infusion of R-enantiomer of ketamine in rat brain regions of learned helplessness model of depression were examined. A single bilateral infusion of R-ketamine into infralimbic (IL) portion of medial prefrontal cortex (mPFC), CA3 and dentate gyrus (DG) of the hippocampus showed antidepressant effects. By contrast, a single bilateral infusion of R-ketamine into prelimbic (PL) portion of mPFC, shell and core of nucleus accumbens, basolateral amygdala and central nucleus of the amygdala had no effect. This study suggests that IL of mPFC, CA3 and DG of hippocampus might be involved in the antidepressant actions of R-ketamine.

Medial prefrontal cortex Transient Receptor Potential Vanilloid Type 1 (TRPV1) in the expression of contextual fear conditioning in Wistar rats

Contextual fear is evoked by re-exposing an animal to an environment that has been previously paired with an aversive or unpleasant stimulus. It can be assessed by freezing and cardiovascular changes such as increase in mean arterial pressure and heart rate. A marked increase in neuronal activity is associated with contextual fear conditioning, especially in limbic structures involved with defense reactions, such as the ventral portion of medial prefrontal cortex. Given the fact that transient receptor potential vanilloid type 1 (TRPV1) receptors could be involved in the expression of defensive behavior, the present work tested the hypothesis that TRPV1 manipulation in the ventromedial prefrontal cortex (vMPFC) modulates the expression of contextual conditioned fear. Male Wistar rats received bilateral microinjections into the vMPFC of the TRPV1 receptor antagonists capsazepine (1, 10, and 60nmol/200nL) or 6-iodonordihydrocapsaicin (3nmol/200nL), and the TRPV1 agonist capsaicin (1nmol/200nL) preceded by vehicle or 6-iodonordihydrocapsaicin before re-exposure to the experimental chamber for 10min, 48h after conditioning in two different protocols distinct by their aversiveness. Both antagonists reduced the freezing and cardiovascular responses in the high aversive protocol. Capsaicin caused an increase in fear-associated responses that could be blocked by 6-iodonordihydrocapsaicin. Our results indicate that TRPV1 receptors located in the vMPFC have a tonic involvement in the modulation of the expression of contextual fear conditioning.

Anxiety-Behavior Modulated by Ventral Medial Prefrontal Cortex of Rats Submitted to the Vogel Conflict Test Involves a Local NMDA Receptor and Nitric Oxide

It was demonstrated in the Vogel conflict test (VCT) that the ventral portion of medial prefrontal cortex (vMPFC) of rats is involved with anxiety behavior. Moreover, the vMPFC local glutamatergic and nitrergic system interaction is involved in modulation of fear conditioning, a model of anxiety. To better understand the role of the MPFC-glutamatergic and nitrergic system on the VTC behavior response, male Wistar rats (250 g) were water deprived for 48 h before the VCT. After 24 h of water deprivation, they were subjected to an initial 3-min non-punished (pre-test) drinking session. Twenty-four hours later bilateral microinjections of NMDA-antagonist LY235959 (4 nmol/200 nL), the specific nNOS inhibitor N-Propyl-L-arginine (N-Propyl –0.08 nmol/200 nL), the NO scavenger Carboxi-PTIO (C-PTIO, 2 nmol/200 nL) or 200nL of vehicle were applied in the vMPFC. After 10 min, the animals were submitted to 3-min punished-licking session. LY235959 increased the number of punished licks. Similar to LY235959, both N-Propyl and C-PTIO also increased the number of punished licks. No changes were observed when LY235959, N-Propyl and C-PTIO were micro- injected into vMPFC surrounding structures such as the cingulate cortex area 1, the corpus callosum and the tenia tecta. In control experiments these drugs did not change neither the number of unpunished licks nor had any effect in the tail-flick test. The results show that NO signaling in the vMPFC can modulate anxiety-behavior in the VCT by control punished behavior. Moreover, this NO modulation could be associated with local glutamatergic activation through NMDA receptors.

Minds Made for Sharing: Initiating Joint Attention Recruits Reward-related Neurocircuitry

The ability and motivation to share attention is a unique aspect of human cognition. Despite its significance, the neural basis remains elusive. To investigate the neural correlates of joint attention, we developed a novel, interactive research paradigm in which participants' gaze behavior--as measured by an eye tracking device--was used to contingently control the gaze of a computer-animated character. Instructed that the character on screen was controlled by a real person outside the scanner, 21 participants interacted with the virtual other while undergoing fMRI. Experimental variations focused on leading versus following the gaze of the character when fixating one of three objects also shown on the screen. In concordance with our hypotheses, results demonstrate, firstly, that following someone else's gaze to engage in joint attention resulted in activation of anterior portion of medial prefrontal cortex (MPFC) known to be involved in the supramodal coordination of perceptual and cognitive processes. Secondly, directing someone else's gaze toward an object activated the ventral striatum which--in light of ratings obtained from participants--appears to underlie the hedonic aspects of sharing attention. The data, therefore, support the idea that other-initiated joint attention relies upon recruitment of MPFC previously related to the "meeting of minds." In contrast, self-initiated joint attention leads to a differential increase of neural activity in reward-related brain areas, which might contribute to the uniquely human motivation to engage in the sharing of experiences.

Different role of the ventral medial prefrontal cortex on modulation of innate and associative learned fear

Reversible inactivation of the ventral portion of medial prefrontal cortex (vMPFC) of the rat brain has been shown to induce anxiolytic-like effects in animal models based on associative learning. The role of this brain region in situations involving innate fear, however, is still poorly understood, with several contradictory results in the literature. The objective of the present work was to verify in male Wistar rats the effects of vMPFC administration of cobalt chloride (CoCl 2), a selective inhibitor of synaptic activity, in rats submitted to two models based on innate fear, the elevated plus-maze (EPM) and light-dark box (LDB), comparing the results with those obtained in two models involving associative learning, the contextual fear conditioning (CFC) and Vogel conflict (VCT) tests. The results showed that, whereas CoCl 2 induced anxiolytic-like effects in the CFC and VCT tests, it enhanced anxiety in rats submitted to the EPM and LDB. Together these results indicate that the vMPFC plays an important but complex role in the modulation of defensive-related behaviors, which seems to depend on the nature of the anxiety/fear inducing stimuli.

The Expression of Contextual Fear Conditioning Involves Activation of an NMDA Receptor-Nitric Oxide Pathway in the Medial Prefrontal Cortex

The ventral portion of medial prefrontal cortex (vMPFC) is involved in contextual fear-conditioning expression in rats. In the present study, we investigated the role of local N-methyl-D-aspartic acid (NMDA) glutamate receptors and nitric oxide (NO) in vMPFC on the behavioral (freezing) and cardiovascular (increase of arterial pressure and heart rate) responses of rats exposed to a context fear conditioning. The results showed that both freezing and cardiovascular responses to contextual fear conditioning were reduced by bilateral administration of NMDA receptor antagonist LY235959 (4 nmol/200 nL) into the vMPFC before reexposition to conditioned chamber. Bilateral inhibition of neuronal NO synthase (nNOS) by local vMPFC administration of the Nω-propyl-L-arginine (N-propyl, 0.04 nmol/200 nL) or the NO scavenger carboxy-PTIO (1 nmol/200 nL) caused similar results, inhibiting the fear responses. We also investigated the effects of inhibiting glutamate- and NO-mediated neurotransmission in the vMPFC at the time of aversive context exposure on reexposure to the same context. It was observed that the 1st exposure results in a significant attenuation of the fear responses on reexposure in vehicle-treated animals, which was not modified by the drugs. The present results suggest that a vMPFC NMDA–NO pathway may play an important role on expression of contextual fear conditioning.

Cardiovascular effects of l-glutamate injected in the medial prefrontal cortex of spontaneously hypertensive rats

We have previously reported that l-glutamate (L-glu) injected into the ventral portion of medial prefrontal cortex (vMPFC) of unanesthetized normotensive Wistar rats elicited cardiovascular responses. In the present study we investigated whether the spontaneously hypertensive rat (SHR) exhibit abnormal cardiovascular responses after L-glu microinjection in the vMPFC. Microinjections of L-glu (3, 9, 27, 81 or 150 nmol/200 nl) caused long-lasting dose-related depressor and bradycardiac responses in unanesthetized SHR (n=6, each dose). Pressor and tachycardiac responses were evoked after the injection of 81 nmol of L-glu in the vMPFC of normotensive Wistar rats (n=6). Systemic pretreatment with the beta1-adrenoceptor antagonist atenolol (1.5 mg/kg, i.v.) had no effect on L-glu cardiovascular responses evoked in the SHR (n=5). However, the treatment with the muscarinic antagonist homatropine methyl bromide (1 mg/kg, i.v.) blocked the bradycardiac response to L-glu, without significant effects on depressor response evoked by L-glu in the SHR (n=5). These results indicate that the bradycardiac response to the injection of L-glu injection in the vMPFC is due to activation of the parasympathetic system and not to inhibition of the cardiac sympathetic input. In conclusion, results indicate opposite cardiovascular responses when L-glu was microinjected in the vMPFC of unanesthetized SHR or normotensive. The bradycardiac response observed in the SHR was due to parasympathetic activation and was not affected by pharmacological blockade of the cardiac sympathetic output.

Injection of l-glutamate into medial prefrontal cortex induces cardiovascular responses through NMDA receptor – nitric oxide in rat

We have reported that l-glutamate ( l-glu) microinjections into ventral portion of medial prefrontal cortex (vMPFC) caused tachycardia and blood pressure increase in unanesthetized rats. In the present study, we report the subtype of vMPFC glutamatergic receptor mediating the response as well as the possible involvement of nitric oxide (NO) in these cardiovascular responses. Microinjection of 200 nL of l-glu (81 nmol) into the vMPFC of unanesthetized rats caused long-lasting pressor and tachycardic responses which were abolished by pretreatment with 4 nmol of the specific NMDA receptor antagonist AP7. The response was not affected by 4 nmol of the non-NMDA receptor antagonist NBQX. Local pretreatment with 80 nmol of the unspecific nitric oxide synthase (NOS) inhibitor NG-nitro- l-arginine methyl ester ( l-NAME) or 0.08 nmol of the specific neuronal NOS (nNOS) inhibitor N ω-Propyl- l-arginine ( N-Propyl) blocked l-glu effects. Microinjection of the NO donor sodium nitroprusside (SNP: 3, 9, 27 or 81 nmol) in the vMPFC caused dose-related long-lasting pressor and tachycardic responses in unanesthetized rats, which were similar to those caused by l-glu. These results suggest that cardiovascular responses evoked by local injection of l-glu into the vMPFC of unanesthetized rats are caused by activation of a local NMDA receptor–NO pathway.

Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats.

The emotional reactivity of rats with lesions of the dorsal portion of medial prefrontal cortex (mPFC) was examined using a classical fear conditioning paradigm. Conditioned fear behavior (freezing responses) was measured during both the acquisition and extinction phases of the task. Lesions enhanced fear reactivity to both the conditioned stimulus (CS) and contextual stimuli during both phases, suggesting that dorsal mPFC lesions produce a general increase in fear reactivity in response to fear conditioning. M. A. Morgan, L. M. Romanski, and J. E. LeDoux (1993) found that lesions just ventral to the present lesions had no effect during acquisition of the same task and prolonged the fear response to the CS (but not the context) during extinction. Thus, both dorsal and ventral regions of mPFC are involved in the fear system, but each modulates different aspects of fear responsivity.