Research progress on the mechanism of pain related neural pathways above the spinal cord / 生理学报

Pain is a multi-dimensional emotional experience, and pain sensation and pain emotion are the two main components. As for pain, previous studies only focused on a certain link of the pain transmission pathway or a certain key brain region, and there is a lack of evidence that connectivity of brain regions is involved in pain or pain regulation in the overall state. The establishment of new experimental tools and techniques has brought light to the study of neural pathways of pain sensation and pain emotion. In this paper, the structure and functional basis of the neural pathways involved in the formation of pain sensation and the regulation of pain emotion in the nervous system above the spinal cord level, including thalamus, amygdala, midbrain periaqueductal gray (PAG), parabrachial nucleus (PB) and medial prefrontal cortex (mPFC), are reviewed in recent years, providing clues for the in-depth study of pain.

The Periaqueductal Gray and Its Extended Participation in Drug Addiction Phenomena / 神经科学通报·英文版

The periaqueductal gray (PAG) is a complex mesencephalic structure involved in the integration and execution of active and passive self-protective behaviors against imminent threats, such as immobility or flight from a predator. PAG activity is also associated with the integration of responses against physical discomfort (e.g., anxiety, fear, pain, and disgust) which occurs prior an imminent attack, but also during withdrawal from drugs such as morphine and cocaine. The PAG sends and receives projections to and from other well-documented nuclei linked to the phenomenon of drug addiction including: (i) the ventral tegmental area; (ii) extended amygdala; (iii) medial prefrontal cortex; (iv) pontine nucleus; (v) bed nucleus of the stria terminalis; and (vi) hypothalamus. Preclinical models have suggested that the PAG contributes to the modulation of anxiety, fear, and nociception (all of which may produce physical discomfort) linked with chronic exposure to drugs of abuse. Withdrawal produced by the major pharmacological classes of drugs of abuse is mediated through actions that include participation of the PAG. In support of this, there is evidence of functional, pharmacological, molecular. And/or genetic alterations in the PAG during the impulsive/compulsive intake or withdrawal from a drug. Due to its small size, it is difficult to assess the anatomical participation of the PAG when using classical neuroimaging techniques, so its physiopathology in drug addiction has been underestimated and poorly documented. In this theoretical review, we discuss the involvement of the PAG in drug addiction mainly via its role as an integrator of responses to the physical discomfort associated with drug withdrawal.

Magnetic Resonance Image Texture Analysis of the Periaqueductal Gray Matter in Episodic Migraine Patients without T2-Visible Lesions

OBJECTIVE: The periaqueductal gray matter (PAG), a small midbrain structure, presents dysfunction in migraine. However, the precise neurological mechanism is still not well understood. Herein, the aim of this study was to investigate the texture characteristics of altered PAG in episodic migraine (EM) patients based on high resolution brain structural magnetic resonance (MR) images. MATERIALS AND METHODS: The brain structural MR images were obtained from 18 normal controls (NC), 18 EM patients and 16 chronic migraine (CM) patients using a 3T MR system. A PAG template was created using the International Consortium Brain Mapping 152 gray matter model, and the individual PAG segment was developed by applying the deformation field from the structural image segment to the PAG template. A grey level co-occurrence matrix was used to calculate the texture parameters including the angular second moment (ASM), contrast, correlation, inverse difference moment (IDM) and entropy. RESULTS: There was a significant difference for ASM, IDM and entropy in the EM group (998.629 ± 0.162 × 10−3, 999.311 ± 0.073 × 10−3, 916.354 ± 0.947 × 10−5) compared to that found in the NC group (998.760 ± 0.110 × 10−3, 999.358 ± 0.037 × 10−3 and 841.198 ± 0.575 × 10−5) (p < 0.05). The entropy was significantly lower among the patients with CM (864.116 ± 0.571 × 10−5) than that found among patients with EM (p < 0.05). The area under the receiver operating characteristic curve was 0.776 and 0.750 for ASM and entropy in the distinction of the EM from NC groups, respectively. ASM was negatively related to disease duration (DD) and the Migraine Disability Assessment Scale (MIDAS) scores in the EM group, and entropy was positively related to DD and MIDAS in the EM group (p < 0.05). CONCLUSION: The present study identified altered MR image texture characteristics of the PAG in EM. The identified texture characteristics could be considered as imaging biomarkers for EM.

Afferent Pathway-Mediated Effect of α1 Adrenergic Antagonist, Tamsulosin, on the Neurogenic Bladder After Spinal Cord Injury / 대한배뇨장애요실금학회지

PURPOSE: The functions of the lower urinary tract (LUT), such as voiding and storing urine, are dependent on complex central neural networks located in the brain, spinal cord, and peripheral ganglia. Thus, the functions of the LUT are susceptible to various neurologic disorders including spinal cord injury (SCI). SCI at the cervical or thoracic levels disrupts voluntary control of voiding and the normal reflex pathways coordinating bladder and sphincter functions. In this context, it is noteworthy that α1-adrenoceptor blockers have been reported to relieve voiding symptoms and storage symptoms in elderly men with benign prostatic hyperplasia (BPH). Tamsulosin, an α1-adrenoceptor blocker, is also considered the most effective regimen for patients with LUT symptoms such as BPH and overactive bladder (OAB). METHODS: In the present study, the effects of tamsulosin on the expression of c-Fos, nerve growth factor (NGF), and nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) in the afferent micturition areas, including the pontine micturition center (PMC), the ventrolateral periaqueductal gray matter (vlPAG), and the spinal cord (L5), of rats with an SCI were investigated. RESULTS: SCI was found to remarkably upregulate the expression of c-Fos, NGF, and NADPH-d in the afferent pathway of micturition, the dorsal horn of L5, the vlPAG, and the PMC, resulting in the symptoms of OAB. In contrast, tamsulosin treatment significantly suppressed these neural activities and the production of nitric oxide in the afferent pathways of micturition, and consequently, attenuated the symptoms of OAB. CONCLUSIONS: Based on these results, tamsulosin, an α1-adrenoceptor antagonist, could be used to attenuate bladder dysfunction following SCI. However, further studies are needed to elucidate the exact mechanism and effects of tamsulosin on the afferent pathways of micturition.

Differential modulation of electrical stimulation of periaqueductal gray and thalamus on nociceptive behaviors of rats / 生理学报

Deep brain stimulation (DBS) is a surgical treatment which has shown remarkable therapeutic benefits for patients with a variety of neurologic conditions. As an important application, DBS has been used to treat intractable pain for over 60 years. Clinical studies have revealed that the selection of the stimulation sites depended on the types of pain. In this study, we selected ventrolateral periaqueductal gray (vlPAG) and ventral posterior lateral nucleus (VPL) as the target brain areas, which were widely used in clinical treatment of refractory pain, to clarify and compare the effects of vlPAG and VPL stimulation on different models of pain. Acute pain was evoked by thermal stimulation. The chronic inflammatory pain was produced by complete Freund's adjuvant (CFA) injection, while neuropathic pain was induced by spinal nerve ligation (SNL) surgery. Some important results emerged from this study: (1) in the experiment of normal rats, we found that unilateral vlPAG stimulation could lead to a significant increase of the thermal withdrawal threshold in bilateral hindpaws of rats, which means a significant bilateral analgesic action; (2) in the CFA test, both contralateral vlPAG and VPL stimulation significantly alleviated the thermal hyperalgesia, which exhibited analgesic effects to the chronic inflammatory pain; (3) in the SNL experiment, the results revealed that contralateral VPL stimulation could significantly abolish the mechanical allodynia induced by SNL, indicating remarkable analgesic effect to neuropathic pain. But the vlPAG stimulation did not have any effect on the mechanical allodynia. These results suggest that the electrical stimulation of the PAG works more effectively on nociceptive pain, including acute pain and chronic inflammatory pain. Besides, the VPL stimulation is much more sensitive for chronic pain, including chronic inflammatory pain and neuropathic pain.

Changes of Mu-opioid receptor and neuron-restrictive silencer factor in periaquductal gray in mouse models of remifentanil-induced postoperative hyperalgesia / 中南大学学报(医学版)

OBJECTIVE@#To determine the changes of Mu-opioid receptor (Mor) and neuron-restrictive silencer factor (NRSF) in periaquductal gray (PAG) in mouse models of remifentanil-induced postoperative hyperalgesia.@*METHODS@#Thirty-two Kun-Ming mice were randomly divided into 4 groups (8 mice in each group): Group C (mice underwent a sham procedure and saline was infused subcutaneously over a period of 30 min), Group I (mice underwent a surgical incision and the same volume of saline), Group R (mice underwent a sham procedure and remifentanil was infused subcutaneously at the moment of surgical incision over a period of 30 min), and group IR (mice underwent a surgical incision and remifentanil). Paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) tests were performed 24 h before the operation and 2, 6, 24, and 48 h after the operation. The specimens were collected after behavioral testings at 48 h. The expressions of Mor and NRSF in mice's PAG neurons were determined by Western blot.@*RESULTS@#Mechanical allodynia and thermal hyperalgesia developed in Group I, R and IR (P<0.01). Intraoperative infusion of remifentanil enhanced mechanical allodynia and thermal hyperalgesia in mice with planta incision (P<0.01). In Group R and Group IR, the expression of Mor was significantly lower (P<0.01) and NRSF was significantly higher (P<0.01) when compared with Group C and Group I.@*CONCLUSION@#Intraoperative infusion of remifentanil induces postoperative hyperalgesia in mouse models, accompanied with decreased expressions of Mor and increased of NRSF level in PAG neurons, which may be involved in remifentanil induced hyperalgesia.

Presence of multiple peripheral circadian oscillators in the tissues controlling voiding function in mice

Circadian clocks are the endogenous oscillators that harmonize a variety of physiological processes within the body. Although many urinary functions exhibit clear daily or circadian variation in diurnal humans and nocturnal rodents, the precise mechanisms of these variations are as yet unclear. In the present study, we demonstrate that Per2 promoter activity clearly oscillates in neonate and adult bladders cultured ex vivo from Per2::Luc knock-in mice. In subsequent experiments, we show that multiple local oscillators are operating in all the bladder tissues (detrusor, sphincter and urothelim) and the lumbar spinal cord (L4-5) but not in the pontine micturition center or the ventrolateral periaqueductal gray of the brain. Accordingly, the water intake and urine volume exhibited daily and circadian variations in young adult wild-type mice but not in Per1-/- Per2-/- mice, suggesting a functional clock-dependent nature of the micturition rhythm. Particularly in PDK mice, the water intake and urinary excretion displayed an arrhythmic pattern under constant darkness, and the amount of water consumed and excreted significantly increased compared with those of WT mice. These results suggest that local circadian clocks reside in three types of bladder tissue and the lumbar spinal cord and may have important roles in the circadian control of micturition function.

Ventrolateral periaqueductal gray metabotropic glutamate receptor subtypes 7 and 8 mediate opposite effects on cardiosomatic motor reflex in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the role of ventrolateral periaqueductal gray (VL-PAG) metabotropic glutamate receptors subtype 7 and 8 (mGluR 7/8) in descending modulation of cardiosomatic motor reflex (CMR) in rats.</p><p><b>METHODS</b>AMN082 (agonist of mGluR 7) and DCPG (agonist of mGluR 8) were injected into the VL-PAG of a rat model of CMR to observe their effects in modulating CMR. The raphe magnus nucleus (NRM) or the gigantocellular reticular nucleus (Gi) was then damaged, and the changes in VL-PAG descending modulation were observed.</p><p><b>RESULTS</b>Selective activation of mGluR 7 of the VL-PAG by AMN082 obviously facilitated capsaicin (CAP)-induced CMR (P<0.05), which was suppressed by DCPG-induced mGluR 8 activation (P<0.05). These facilitatory or inhibitory effects were completely reversed by group III mGluR antagonist MSOP. Damaging the NRM of VL-PAG main relay nucleus did not significantly affect the facilitatory effect produced by AMN082 microinjection (P>0.05), but partially attenuated the inhibitory effect of DCPG microinjection (P<0.05). Both the facilitatory effect of AMN082 and the inhibitory effect of DCPG were reduced obviously after bilateral Gi damage (P<0.05).</p><p><b>CONCLUSION</b>VL-PAG mGluR 7 and mGluR 8 mediate biphasic regulation of CMR in rats probably through activation of different sub-nuclei and different neurons in the rostroventral medulla.</p>

Changes in c-Fos Expression in the Forced Swimming Test: Common and Distinct Modulation in Rat Brain by Desipramine and Citalopram

Rodents exposed to a 15-min pretest swim in the forced swimming test (FST) exhibit prolonged immobility in a subsequent 5-min test swim, and antidepressant treatment before the test swim reduces immobility. At present, neuronal circuits recruited by antidepressant before the test swim remain unclear, and also less is known about whether antidepressants with different mechanisms of action could influence neural circuits differentially. To reveal the neural circuits associated with antidepressant effect in the FST, we injected desipramine or citalopram 0.5 h, 19 h, and 23 h after the pretest swim and observed changes in c-Fos expression in rats before the test swim, namely 24 h after the pretest swim. Desipramine treatment alone in the absence of pretest swim was without effect, whereas citalopram treatment alone significantly increased the number of c-Fos-like immunoreactive cells in the central nucleus of the amygdala and bed nucleus of the stria terminalis, where this pattern of increase appears to be maintained after the pretest swim. Both desipramine and citalopram treatment after the pretest swim significantly increased the number of c-Fos-like immunoreactive cells in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim. These results suggest that citalopram may affect c-Fos expression in the central nucleus of the amygdala and bed nucleus of the stria terminalis distinctively and raise the possibility that upregulation of c-Fos in the ventral lateral septum and ventrolateral periaqueductal gray before the test swim may be one of the probable common mechanisms underlying antidepressant effect in the FST.

A Case of Thiamine (Vitamin B1)-Deficient Optic Neuropathy Associated with Wernicke's Encephalopathy

PURPOSE: To report a case of subacute optic neuropathy caused by thiamine (vitamin B1) deficiency. CASE SUMMARY: A 44-year-old woman was referred to the ophthalmology department due to decreased vision which began 10 days prior to presentation. The patient history indicated that she had undergone chemotherapy for ovarian cancer and she had been dependent on total parenteral nutrition for 3 weeks due to nausea and vomiting. Her best corrected vision of the right and the left eyes were 0.15 and 0.2, respectively. Color vision was severely impaired in both eyes without retrobulbar pain. There was marginal blurring on the temporal side of the optic discs of both eyes. The optic nerves were unremarkable on orbital and brain magnetic resonance imaging (MRI). There was high signal intensities in both the mammillary body and periaqueductal gray matter on T2-weighted imaging. In addition, the patient exhibited ataxia along with short-term memory loss. She was diagnosed with Wernicke's encephalopathy. Thiamine was administrated based on the diagnosis, and after 2 days of administration, the patient's vision and neurologic symptoms began to improve. Two weeks later, the patient recovered her vision. CONCLUSIONS: Thiamine deficiency may cause optic neuropathy and can be recovered with early thiamine supplementation. This condition could occur due to deficient oral thiamine administration. We should keep this point in mind and try to prevent or diagnose early.

Switching from morphine to fentanyl attenuates the decline of µ-opioid receptor expression in periaqueductal gray of rats with morphine tolerance / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Opioid switching is a therapeutic maneuver to improve analgesic response and/or reduce adverse side effects although the underlying mechanisms remain unknown. The µ-opioid receptor (MOR) has an important role in mediating the actions of morphine and other analgesic agents. This study is aimed at exploring the changes of MOR in the periaqueductal gray (PAG) in rats when morphine is substituted for equianalgesic fentanyl.</p><p><b>METHODS</b>Forty rats were randomly assigned to five treatment groups: 7 days normal saline group (N group), 7 days fentanyl group (F group), 7 days morphine group (M group), 7 days morphine and 7 days fentanyl-switching group (MF group), and 14 days morphine group (MM group). Rats repeatedly received subcutaneous injections of morphine sulfate (10 mg/kg) or equianalgesic fentanyl sulfate (0.1 mg/kg) twice daily. Rats' antinociceptive response to thermal pain was evaluated by the tail flick latency assay. MOR mRNA and protein expression in the PAG were measured using RT-PCR and Western blotting analyses respectively.</p><p><b>RESULTS</b>This study showed that after morphine was substituted with fentanyl on day 8, the tail flick latency (TFL) increased from (3.9 ± 0.4) seconds to (11.4 ± 0.4) seconds. The results also demonstrated that both MOR mRNA and protein expression in the PAG of rats in the MF group were less than that in the M group (P < 0.05) but more than that in MM group (P < 0.05).</p><p><b>CONCLUSIONS</b>Equianalgesic fentanyl was still antinociceptive effective in rats with morphine tolerance, which may be due to the switching from morphine to fentanyl attenuating the decline of MOR expression in the PAG of rats.</p>

Dorsal periaqueductal gray stimulation facilitates anxiety-, but not panic-related, defensive responses in rats tested in the elevated T-maze

The escape response to electrical or chemical stimulation of the dorsal periaqueductal gray matter (DPAG) has been associated with panic attacks. In order to explore the validity of the DPAG stimulation model for the study of panic disorder, we determined if the aversive consequences of the electrical or chemical stimulation of this midbrain area can be detected subsequently in the elevated T-maze. This animal model, derived from the elevated plus-maze, permits the measurement in the same rat of a generalized anxiety- and a panic-related defensive response, i.e., inhibitory avoidance and escape, respectively. Facilitation of inhibitory avoidance, suggesting an anxiogenic effect, was detected in male Wistar rats (200-220 g) tested in the elevated T-maze 30 min after DPAG electrical stimulation (current generated by a sine-wave stimulator, frequency at 60 Hz) or after local microinjection of the GABA A receptor antagonist bicuculline (5 pmol). Previous electrical (5, 15, 30 min, or 24 h before testing) or chemical stimulation of this midbrain area did not affect escape performance in the elevated T-maze or locomotion in an open-field. No change in the two behavioral tasks measured by the elevated T-maze was observed after repetitive (3 trials) electrical stimulation of the DPAG. The results indicate that activation of the DPAG caused a short-lived, but selective, increase in defensive behaviors associated with generalized anxiety.

Behavioral meaningful opioidergic stimulation activates kappa receptor gene expression

The periaqueductal gray (PAG) has been reported to be a location for opioid regulation of pain and a potential site for behavioral selection in females. Opioid-mediated behavioral and physiological responses differ according to the activity of opioid receptor subtypes. The present study investigated the effects of the peripheral injection of the kappa-opioid receptor agonist U69593 into the dorsal subcutaneous region of animals on maternal behavior and on Oprk1 gene activity in the PAG of female rats. Female Wistar rats weighing 200-250 g at the beginning of the study were randomly divided into 2 groups for maternal behavior and gene expression experiments. On day 5, pups were removed at 7:00 am and placed in another home cage that was distant from their mother. Thirty minutes after removing the pups, the dams were treated with U69593 (0.15 mg/kg, sc) or 0.9% saline (up to 1 mL/kg) and after 30 min were evaluated in the maternal behavior test. Latencies in seconds for pup retrieval, grouping, crouching, and full maternal behavior were scored. The results showed that U69593 administration inhibited maternal behavior (P < 0.05) because a lower percentage of kappa group dams showed retrieval of first pup, retrieving all pups, grouping, crouching and displaying full maternal behavior compared to the saline group. Opioid gene expression was evaluated using real-time reverse-transcription polymerase chain reaction (RT-PCR). A single injection of U69593 increased Oprk1 PAG expression in both virgin (P < 0.05) and lactating female rats (P < 0.01), with no significant effect on Oprm1 or Oprd1 gene activity. Thus, the expression of kappa-opioid receptors in the PAG may be modulated by single opioid receptor stimulation and behavioral meaningful opioidergic transmission in the adult female might occur simultaneously to specific changes in gene expression of kappa-opioid receptor subtype. This is yet another alert for the complex role of the opioid ...

Involvement of midbrain tectum neurokinin-mediated mechanisms in fear and anxiety

Electrical stimulation of midbrain tectum structures, particularly the dorsal periaqueductal gray (dPAG) and inferior colliculus (IC), produces defensive responses, such as freezing and escape behavior. Freezing also ensues after termination of dPAG stimulation (post-stimulation freezing). These defensive reaction responses are critically mediated by γ-aminobutyric acid and 5-hydroxytryptamine mechanisms in the midbrain tectum. Neurokinins (NKs) also play a role in the mediation of dPAG stimulation-evoked fear, but how NK receptors are involved in the global processing and expression of fear at the level of the midbrain tectum is yet unclear. The present study investigated the role of NK-1 receptors in unconditioned defensive behavior induced by electrical stimulation of the dPAG and IC of male Wistar rats. Spantide (100 pmol/0.2 μL), a selective NK-1 antagonist, injected into these midbrain structures had anti-aversive effects on defensive responses and distress ultrasonic vocalizations induced by stimulation of the dPAG but not of the IC. Moreover, intra-dPAG injections of spantide did not influence post-stimulation freezing or alter exploratory behavior in rats subjected to the elevated plus maze. These results suggest that NK-1 receptors are mainly involved in the mediation of defensive behavior organized in the dPAG. Dorsal periaqueductal gray-evoked post-stimulation freezing was not affected by intra-dPAG injections of spantide, suggesting that NK-1-mediated mechanisms are only involved in the output mechanisms of defensive behavior and not involved in the processing of ascending aversive information from the dPAG.

Contrasting effects of nitric oxide and corticotropin- releasing factor within the dorsal periaqueductal gray on defensive behavior and nociception in mice

The anxiogenic and antinociceptive effects produced by glutamate N-methyl-D-aspartate receptor activation within the dorsal periaqueductal gray (dPAG) matter have been related to nitric oxide (NO) production, since injection of NO synthase (NOS) inhibitors reverses these effects. dPAG corticotropin-releasing factor receptor (CRFr) activation also induces anxiety-like behavior and antinociception, which, in turn, are selectively blocked by local infusion of the CRF type 1 receptor (CRFr1) antagonist, NBI 27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)aminopyridine]. Here, we determined whether i) the blockade of the dPAG by CRFr1 attenuates the anxiogenic/antinociceptive effects induced by local infusion of the NO donor, NOC-9 [6-(2-hydroxy-1-methyl-2-nitrosohydrazino)-N-methyl-1-hexanamine], and ii) the anxiogenic/antinociceptive effects induced by intra-dPAG CRF are prevented by local infusion of Nω-propyl-L-arginine (NPLA), a neuronal NOS inhibitor, in mice. Male Swiss mice (12 weeks old, 25-35 g, N = 8-14/group) were stereotaxically implanted with a 7-mm cannula aimed at the dPAG. Intra-dPAG NOC-9 (75 nmol) produced defensive-like behavior (jumping and running) and antinociception (assessed by the formalin test). Both effects were reversed by prior local infusion of NBI 27914 (2 nmol). Conversely, intra-dPAG NPLA (0.4 nmol) did not modify the anxiogenic/antinociceptive effects of CRF (150 pmol). These results suggest that CRFr1 plays an important role in the defensive behavior and antinociception produced by NO within the dPAG. In contrast, the anxiogenic and antinociceptive effects produced by intra-dPAG CRF are not related to NO synthesis in this limbic midbrain structure.

New perspective on the pathophysiology of panic: merging serotonin and opioids in the periaqueductal gray

Panic disorder patients are vulnerable to recurrent panic attacks. Two neurochemical hypotheses have been proposed to explain this susceptibility. The first assumes that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organize defensive reactions to cope with proximal threats and of sympathomotor control areas of the rostral ventrolateral medulla that generate most of the neurovegetative symptoms of the panic attack. The second suggests that endogenous opioids buffer normal subjects from the behavioral and physiological manifestations of the panic attack, and their deficit brings about heightened suffocation sensitivity and separation anxiety in panic patients, making them more vulnerable to panic attacks. Experimental results obtained in rats performing one-way escape in the elevated T-maze, an animal model of panic, indicate that the inhibitory action of serotonin on defense is connected with activation of endogenous opioids in the periaqueductal gray. This allows reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology, the periaqueductal gray being the fulcrum of serotonin-opioid interaction.

Fine-tuning of defensive behaviors in the dorsal periaqueductal gray by atypical neurotransmitters

This paper presents an up-to-date review of the evidence indicating that atypical neurotransmitters such as nitric oxide (NO) and endocannabinoids (eCBs) play an important role in the regulation of aversive responses in the periaqueductal gray (PAG). Among the results supporting this role, several studies have shown that inhibitors of neuronal NO synthase or cannabinoid receptor type 1 (CB1) receptor agonists cause clear anxiolytic responses when injected into this region. The nitrergic and eCB systems can regulate the activity of classical neurotransmitters such as glutamate and γ-aminobutyric acid (GABA) that control PAG activity. We propose that they exert a ‘fine-tuning’ regulatory control of defensive responses in this area. This control, however, is probably complex, which may explain the usually bell-shaped dose-response curves observed with drugs that act on NO- or CB1-mediated neurotransmission. Even if the mechanisms responsible for this complex interaction are still poorly understood, they are beginning to be recognized. For example, activation of transient receptor potential vanilloid type-1 channel (TRPV1) receptors by anandamide seems to counteract the anxiolytic effects induced by CB1 receptor activation caused by this compound. Further studies, however, are needed to identify other mechanisms responsible for this fine-tuning effect.

What ethologically based models have taught us about the neural systems underlying fear and anxiety

Classical Pavlovian fear conditioning to painful stimuli has provided the generally accepted view of a core system centered in the central amygdala to organize fear responses. Ethologically based models using other sources of threat likely to be expected in a natural environment, such as predators or aggressive dominant conspecifics, have challenged this concept of a unitary core circuit for fear processing. We discuss here what the ethologically based models have told us about the neural systems organizing fear responses. We explored the concept that parallel paths process different classes of threats, and that these different paths influence distinct regions in the periaqueductal gray - a critical element for the organization of all kinds of fear responses. Despite this parallel processing of different kinds of threats, we have discussed an interesting emerging view that common cortical-hippocampal-amygdalar paths seem to be engaged in fear conditioning to painful stimuli, to predators and, perhaps, to aggressive dominant conspecifics as well. Overall, the aim of this review is to bring into focus a more global and comprehensive view of the systems organizing fear responses.

Aplicación clínica de las imágenes de resonancia magnética potenciadas en difusión y tractografía en un niño con holoprosencefalia / Clinical application of diffusion tensor imaging and tractography in a child with holoprosencephal

Las imágenes de resonancia magnética potenciadas en difusión y tractografía pueden emplearse en el estudio de las malformaciones congénitas del sistema nervioso central asociadas a anormalidades en los tractos de sustancia blanca. Presentamos un paciente con holoprosencefalia semilobar en quien la imagen potenciada en difusión y la tractografía demostró falla de la inducción ventral del prosencéfalo y fusión anormal de varios fascículos de la sustancia blanca en el cerebro y en el tallo encefálico. De esta forma, las anormalidades de los fascículos de la sustancia blanca en casos de holoprosencefalia se pueden identificar por medio de las imágenes potenciadas en difusión y tractografía fasciculografía.

Diffusion tensor imaging and fiber tracking can be methods used for the study of congenital brain malformations associated to white matter bundle abnormalities.Their use is illustrated in a child with semilobar holoprosencephaly in whom diffusion tensor imaging and tractography showed diencephalic ventral induction failure and abnormal white matter fascicles in brain and brainstem.

Fear, anxiety and their disorders: past, present and future neural theories

This paper reviews the historical development of a two-dimensional (direction x distance (?)) neural model of defense. It begins with Miller's (1944) analysis, and model, of approach, avoidance and conflict; adds Hinde's (1966) ethological perspective and Flynn's (1967) neural model of fear; and then considers Gray's (1967, 1970) work linking barbiturate action to the hippocampus, McNaughton's (1977) extension of this to other classes of anxiolytics, and Gray & McNaughton's (1983) detailed behavioral comparison of anxiolytics and hippocampal lesions. This work led to Gray's (1982) detailed model of the neuropsychology of anxiety. Rapoport's (1989) model of the control of obsession by the cingulate cortex, and Ledoux's (1994) model of the control of both fear and anxiety to the amygdala, suggested a more complex organisation of defense systems. McNaughton (1989) argued that evolutionary function defines an emotion, and Blanchard and Blanchard (1990) argued for its assessment via ethoexperimental analysis. Graeff (1994) then produced a neural model that mapped defensive distance to neural level, treating all anxiety as being at a greater defensive distance than fear. Seeing this, and the treatment of anxiety as due to uncertainty (which is inconsistent with Miller's data), as being unsatisfactory, Gray and McNaughton (2000) and then McNaughton and Corr (2004) developed the two-dimensional model of defensive systems. This model is clearly incomplete at the present time and its links with neuroeconomics, personality, and stress and greater specification of frontal cortical contributions are suggested as directions for future development.