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Rats produce robust, highly distinctive orofacial rhythms in response to taste stimuli-responses that aid in the consumption of palatable tastes and the ejection of aversive tastes, and that are sourced in a multifunctional brainstem central pattern generator. Several pieces of indirect evidence suggest that primary gustatory cortex (GC) may be a part of a distributed forebrain circuit involved in the selection of particular consumption-related rhythms, although not in the production of individual mouth movements per se. Here, we performed a series of tests of this hypothesis. We first examined the temporal relationship between GC activity and orofacial behaviors by performing paired single-neuron and electromyographic recordings in awake rats. Using a trial-by-trial analysis, we found that a subset of GC neurons shows a burst of activity beginning before the transition between nondistinct and taste-specific (i.e., consumption-related) orofacial rhythms. We further showed that shifting the latency of consumption-related behavior by selective cueing has an analogous impact on the timing of GC activity. Finally, we showed the complementary result, demonstrating that optogenetic perturbation of GC activity has a modest but significant impact on the probability that a specific rhythm will be produced in response to a strongly aversive taste. GC appears to be a part of a distributed circuit that governs the selection of taste-induced orofacial rhythms. ⋯ In many well studied (typically invertebrate) sensorimotor systems, top-down modulation helps motor-control regions "select" movement patterns. Here, we provide evidence that gustatory cortex (GC) may be part of the forebrain circuit that performs this function in relation to oral behaviors ("gapes") whereby a substance in the mouth is rejected as unpalatable. We show that GC palatability coding is well timed to play this role, and that the latency of these codes changes as the latency of gaping shifts with learning. We go on to show that by silencing these neurons, we can change the likelihood of gaping. These data help to break down the sensory/motor divide by showing a role for sensory cortex in the selection of motor behavior.
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Uncontrollable, compared with controllable, painful stimulation can lead to increased pain perception and activation in pain-processing brain regions, but it is currently unknown which brain areas mediate this effect. When pain is controllable, the lateral prefrontal cortex (PFC) seems to inhibit pain processing, although it is unclear how this is achieved. Using fMRI in healthy volunteers, we examined brain activation during controllable and uncontrollable stimulation to answer these questions. In the controllable task, participants self-adjusted temperatures applied to their hand of pain or warm intensities to provoke a constant sensation. In the uncontrollable task, the temperature time courses of the controllable task were replayed (yoked control) and participants rated their sensation continuously. During controllable pain trials, participants significantly downregulated the temperature to keep their sensation constant. Despite receiving the identical nociceptive input, intensity ratings increased during the uncontrollable pain trials. This additional sensitization was mirrored in increased activation of pain-processing regions such as insula, anterior cingulate cortex, and thalamus. Further, increased connectivity between the anterior insula and medial PFC (mPFC) in the uncontrollable and increased negative connectivity between dorsolateral PFC (dlPFC) and insula in the controllable task were observed. This suggests a pain-facilitating role of the mPFC during uncontrollable pain and a pain-inhibiting role of the dlPFC during controllable pain, both exerting their respective effects via the anterior insula. These results elucidate neural mechanisms of context-dependent pain modulation and their relation to subjective perception. ⋯ Pain control is of uttermost importance and stimulus controllability is an important way to achieve endogenous pain modulation. Here, we show differential effects of controllability and uncontrollability on pain perception and cerebral pain processing. When pain was controllable, the dorsolateral prefrontal cortex downregulated pain-evoked activation in important pain-processing regions. In contrast, sensitization during uncontrollable pain was mediated by increased connectivity of the medial prefrontal cortex with the anterior insula and other pain-processing regions. These novel insights into cerebral pain modulation by stimulus controllability have the potential to improve treatment approaches in pain patients.
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Mounting evidence from both humans and rodents suggests that tissue damage during the neonatal period can "prime" developing nociceptive pathways such that a subsequent injury during adulthood causes an exacerbated degree of pain hypersensitivity. However, the cellular and molecular mechanisms that underlie this priming effect remain poorly understood. Here, we demonstrate that neonatal surgical injury relaxes the timing rules governing long-term potentiation (LTP) at mouse primary afferent synapses onto mature lamina I projection neurons, which serve as a major output of the spinal nociceptive network and are essential for pain perception. In addition, whereas LTP in naive mice was only observed if the presynaptic input preceded postsynaptic firing, early tissue injury removed this temporal requirement and LTP was observed regardless of the order in which the inputs were activated. Neonatal tissue damage also reduced the dependence of spike-timing-dependent LTP on NMDAR activation and unmasked a novel contribution of Ca(2+)-permeable AMPARs. These results suggest for the first time that transient tissue damage during early life creates a more permissive environment for the production of LTP within adult spinal nociceptive circuits. This persistent metaplasticity may promote the excessive amplification of ascending nociceptive transmission to the mature brain and thereby facilitate the generation of chronic pain after injury, thus representing a novel potential mechanism by which early trauma can prime adult pain pathways in the CNS. ⋯ Tissue damage during early life can "prime" developing nociceptive pathways in the CNS, leading to greater pain severity after repeat injury via mechanisms that remain poorly understood. Here, we demonstrate that neonatal surgical injury widens the timing window during which correlated presynaptic and postsynaptic activity can evoke long-term potentiation (LTP) at sensory synapses onto adult lamina I projection neurons, which serve as a major output of the spinal nociceptive circuit and are essential for pain perception. This persistent increase in the likelihood of LTP induction after neonatal injury is predicted to favor the excessive amplification of ascending nociceptive transmission to the mature brain in response to subsequent injury and thereby exacerbate chronic pain.
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The embryonic ventricular and subventricular zones (VZ/SVZ) contain the neuronal stem and progenitor cells and undergo rapid proliferation. The intermediate zone (IZ) contains nonreplicating, differentiated cells. The VZ/SVZ is hypersensitive to radiation-induced apoptosis. ⋯ We demonstrate a functional G(2)/M checkpoint in VZ/SVZ cells and show that it is not activated by low numbers of DSBs, allowing damaged VZ/SVZ cells to transit into the IZ. We propose a novel model in which microcephaly in LIG4 syndrome arises from sensitive apoptotic induction from persisting DSBs in the IZ, which arise from high endogenous breakage in the VZ/SVZ and transit of damaged cells to the IZ. The VZ/SVZ, in contrast, is highly sensitive to acute radiation-induced DSB formation.
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J. Neuroendocrinol. · Jul 1995
Neuronal activity and neuropeptide gene transcription in the brains of immune-challenged rats.
The present study investigated the effect of the acute-phase response of a systemic immune activation on the transcription of various immediate early genes (IEGs) and neuropeptides in the brain of conscious rats. One, 3, 6, 9, and 12 h after a single intraperitoneal (i.p.) administration of either the immune activator lipopolysaccharide (LPS) or the vehicle solution, adult male rats were sacrificed and their brains cut in 30-microns coronal sections. mRNA encoding the IEGs c-fos and nerve growth factor inducible-B (NGFI-B), and neuropeptides corticotropin-releasing factor (CRF), oxytocin (OT), and vasopressin (AVP) were assayed by in situ hybridization histochemistry using a 35S-labeled riboprobes. The primary transcripts [heteronuclear (hn)RNA] for these neuropeptides were also detected using intronic probe technology, and colocalization of c-fos mRNA within CRF, AVP, and OT neurons was determined by means of a combination of immunocytochemistry and in situ hybridization techniques on same the brain sections. ⋯ The signal for c-fos and NGFI-B mRNA in most of these brain nuclei reached a maximum at 3 h postinjection, declined at 6 h, and vanished 9 to 12 h after LPS treatment. In the parvocellular nucleus of the PVN, c-fos was largely expressed in CRF-immunoreactive (ir) neurons, whereas in the magnocellular part of that nucleus and in the SON, this transcript was colocalized in numerous OT-ir and few AVP-ir neurons. Relative levels of CRF mRNA in the parvocellular PVN were also significantly increased 6 h following LPS, but endotoxin did not alter the genetic expression of this stress-related neuropeptide in other brain regions.(ABSTRACT TRUNCATED AT 400 WORDS)