Most neuronal interactions in the cortex occur within local circuits. Because principal cells and GABAergic interneurons contribute differently to cortical operations, their experimental identification and separation is of utmost important. We used 64-site two-dimensional silicon probes for high-density recording of local neurons in layer 5 of the somatosensory and prefrontal cortices of the rat. Multiple-site monitoring of units allowed for the determination of their two-dimensional spatial position in the brain. Of the approximately 60,000 cell pairs recorded, 0.2% showed robust short-term interactions. Units with significant, short-latency (<3 ms) peaks following their action potentials in their cross-correlograms were characterized as putative excitatory (pyramidal) cells. Units with significant suppression of spiking of their partners were regarded as putative GABAergic interneurons. A portion of the putative interneurons was reciprocally connected with pyramidal cells. Neurons physiologically identified as inhibitory and excitatory cells were used as templates for classification of all recorded neurons. Of the several parameters tested, the duration of the unfiltered (1 Hz to 5 kHz) spike provided the most reliable clustering of the population. High-density parallel recordings of neuronal activity, determination of their physical location and their classification into pyramidal and interneuron classes provide the necessary tools for local circuit analysis.
Migraine is a chronic disease with episodic manifestations. In a subgroup, attack frequency increases over time, leading to chronic migraine. One of the most important risk factors for migraine progression is frequency of headache attacks at baseline. Unfortunately, the actual effects of repeated activation of dural nociceptors are poorly known. We investigated the behavioral, anatomical, and electrophysiological changes induced by repeated low- and high-intensity stimulation of meningeal nociceptor by injecting an inflammatory soup in rats. Single high-intensity, but not low-intensity, stimulation produces a reversible cephalic allodynia. Upon repetition, however, low-intensity stimulation, too, induces a reversible cephalic allodynia, and high-intensity, reversible cephalic and extracephalic allodynia. Moreover, cephalic allodynia becomes, in part, persistent upon repeated high-intensity stimulation. Fos expression reveals that a single high-intensity stimulation already leads to widespread, trigeminal, and spinal central sensitization, and that such general central sensitization potentiates upon repetition. Trigeminovascular nociceptive neurons become persistently sensitized and their diffuse noxious inhibitory controls (DNIC) concomitantly impaired. Thus, compared with single stimulation, repeated dural nociceptor activation specifically leads to: 1) a gradual worsening of cutaneous hypersensitivity and general neuronal hyperexcitability and 2) spreading of cutaneous hypersensitivity superimposed on 3) persistent cephalic cutaneous hypersensitivity and trigeminal central sensitization. Such repetition-induced development of central sensitization and its consequence, cutaneous allodynia, may arise from both the general neuronal hyperexcitability that results from DNIC impairment and hyperexcitability that likely develops in trigeminal nociceptive neurons in response to their repetitive activation. These neuronal changes may in turn elevate the risk for developing chronic migraine.
Oscillatory spike timing in the hippocampus is regarded as a temporal coding mechanism for space, but the underlying mechanisms are poorly understood. To contrast the predictions of the different models of phase precession, we transiently turned off neuronal discharges for up to 250 ms and reset the phase of theta oscillations by stimulating the commissural pathway in rats. After recovery from silence, phase precession continued. The phase of spikes for the first theta cycle after the perturbation was more advanced than the phase of spikes for the last theta cycle just before the perturbation. These findings indicate that phase advancement that emerges within hippocampal circuitry may be updated at the beginning of each theta cycle by extrahippocampal inputs.
The transfer of nociceptive information at the level of dorsal horn is subject to extensive processing by both local segmental and supraspinal mechanisms, including descending dopaminergic controls, originating from the hypothalamic A11 nucleus. The inhibitory role of dopamine on evoked pain via activation of D2-like receptors at the level of the dorsal horn is well established. Here, by use of behavioral, electrophysiological, and anatomical techniques, we examined within the trigeminal sensory complex, first, whether descending dopaminergic controls also modulate pain behavior after an inflammatory insult, and second, under which physiological conditions these descending dopaminergic controls are actually recruited. We show that D2 receptors are mostly located within superficial medullary dorsal horn where trigeminal nociceptive fibers abut. Activating these D2-like receptors inhibits, whereas blocking them enhances, both formalin- and capsaicin-evoked pain behavior and C-fiber-evoked action potential firing of trigeminal wide dynamic range (WDR) neurons. Moreover, windup and diffuse noxious inhibitory controls (DNIC), 2 dynamic properties of C-fiber-evoked firing of WDR neurons, are inhibited by activating and blocking, respectively, these D2-like receptors. Altogether, our results are consistent with a tonic inhibition of the trigeminal nociceptive input by descending dopaminergic controls via activation of D2-like receptors at the level of superficial medullary dorsal horn. Such dopamine-dependent tonic inhibition of nociceptive information can be dynamically modulated by pain. This suggests that dysregulation of descending dopaminergic controls should translate in patients into diffuse, cephalic, and extracephalic pain symptoms--spontaneous pain, decreased pain thresholds, deficient DNIC, or some combination of these.
This study investigates the physiological properties of parabrachial internal lateral (PBil) neurons that project to the paracentral thalamic (PC) nucleus using antidromic activation and single-unit recording techniques in anesthetized rat. We reported here that most of these neurons responded exclusively to the nociceptive stimulation of large receptive fields with a sustained firing that often outlasted the stimulus up to several minutes. These responses were depressed by intravenous morphine.Our results demonstrated a novel spino-PBil-PC pathway, which transmits nociceptive messages to the PC nucleus, which in turn projects to the prefrontal cortex. Recent clinical imaging studies showed the important participation of prefrontal cortex in emotional response to pain. This spino-PBil-PC pathway may explain how nociceptive messages reach the prefrontal cortex and thus trigger unbearable aversive aspects of pain.
Descending pain-modulatory systems, either inhibitory or facilitatory, play a critical role in both acute and chronic pain. Compared with serotonin and norepinephrine, little is known about the function of dopamine (DA). We characterized the anatomical organization of descending DA pathways from hypothalamic A11 nuclei to the medullary dorsal horn (MDH) and investigated their role in trigeminal pain. Immunochemistry analysis reveals that A11 is a heterogeneous nucleus that contains at least 3 neuronal phenotypes, DA, GABA, and alpha-calcitonin gene-related peptide (α-CGRP) neurons, exhibiting different distribution patterns, with a large proportion of GABA relative to DA neurons. Using fluorogold, we show that descending pathways from A11 nuclei to MDH originate mainly from DA neurons and are bilateral. Facial nociceptive stimulation elevates Fos immunoreactivity in both ipsilateral and contralateral A11 nuclei. Fos immunoreactivity is not detected in DA or projecting neurons but, interestingly, in GABA neurons. Finally, inactivating A11, using muscimol, or partially lesioning A11 DA neurons, using the neurotoxin 6-hydroxydopamine, inhibits trigeminal pain behavior. These results show that A11 nuclei are involved in pain processing. Interestingly, however, pain seems to activate GABAergic neurons within A11 nuclei, which suggests that pain inhibits rather than activates descending DA controls. We show that such inhibition produces an antinociceptive effect. Pain-induced inhibition of descending DA controls and the resulting reduced DA concentration within the dorsal horn may inhibit the transfer of nociceptive information to higher brain centers through preferential activation of dorsal horn D2-like receptors.
The somatosensory properties of ventromedial (VM) thalamic neurons were investigated in anesthetized rats by examining their responses to calibrated cutaneous stimuli. A population of neurons within the lateral part of the ventromedial thalamus (VMl) showed two peaks of activation after percutaneous electrical stimuli, regardless of which part of the body was stimulated. The early and late peaks were elicited by Adelta- and C-fiber activities with mean conduction velocities of 12.9 +/- 0.9 and 1 +/- 0.2 m/sec, respectively. These responses were strongly depressed or blocked after microinjections within the medullary subnucleus reticularis dorsalis of xylocaine or the NMDA antagonist MK-801. None of the VMl neurons responded to innocuous cutaneous or proprioceptive stimuli. In contrast, all these neurons responded to noxious mechanical and thermal stimulation of the limbs and showed monotonic increases in their discharges to increasingly strong noxious cutaneous stimuli. In addition, some VMl neurons were antidromically activated by stimulation in layer I of the dorsolateral frontal cortex. These findings suggest that the rat VMl conveys and encodes cutaneous nociceptive inputs from any part of the body surface to layer I of the dorsolateral neocortex. This reticulo-thalamo-cortical network may allow any signal of pain to gain access to widespread areas of the neocortex and thus help prime the cortex for attentional reactions and/or the coordination of motor responses.
Sensory maps for pain can be modified by deafferentation or injury, and such plasticity has been attributed mainly to changes in the convergence of projections in "bottom-up" mechanisms. We addressed the possible contribution of "top-down" mechanisms by investigating the functional significance of corticofugal influences from the primary somatosensory cortex (S1) to the ventroposterolateral thalamic nucleus (VPL). The strong convergence of spinal and lemniscal afferents to the VPL and the close correspondence between afferents and efferents within the VPL-S1 network suggest the existence of functionally related thalamocortical circuits that are implicated in the detection of innocuous and noxious inputs. Functional characterization of single nociceptive, wide dynamic range, and non-nociceptive VPL neurons and labeling the axons and terminal fields with the juxtacellular technique showed that all three types of cells project to a restricted area, within S1. The convergence of the terminal trees of axons from VPL neurons activated by innocuous, noxious, or both inputs suggests that their inputs are not segregated into anatomically distinct regions. Microinjections within S1 were performed for pharmacological manipulation of corticofugal modulation. Glutamatergic activation of corticofugal output enhanced noxious-evoked responses and affected in a biphasic way tactile-evoked responses of VPL cells. GABA A -mediated depression of corticofugal output concomitantly depressed noxious and enhanced innocuous-evoked responses of VPL neurons. Microinjections of a GABA A antagonist on corticofugal cells enhanced noxious-evoked responses of VPL cells. Our findings demonstrate that corticofugal influences from S1 contribute to selectively modulate somatosensory submodalities at the thalamic level.
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