Orexinergic neurons are involved in the chemosensory control of breathing during the dark phase in a Parkinson's disease model.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra compacta (SNpc) and the only risk factor is aging. We showed that in 6-hydroxydopamine (6-OHDA)-model of PD there is a reduction in the neuronal profile within the brainstem ventral respiratory column with a decrease in the hypercapnic ventilatory response. Here we tested the involvement of orexin cells from the lateral hypothalamus/perifornical area (LH/PeF) on breathing in a 6-OHDA PD model. In this model of PD, there is a reduction in the total number of orexinergic neurons and in the number of orexinergic neurons that project to the RTN, without changing the number of CO2-activated orexinergic neurons during the dark phase. The ventilation at rest and in response to hypercapnia (7% CO2) was assessed in animals that received 6-OHDA or vehicle injections into the striatum and saporin anti-Orexin-B or IgG saporin into the LH/PeF during the sleep and awake states. The experiments showed a reduction of respiratory frequency (fR) at rest during the light phase in PD animals only during sleep. During the dark phase, there was an impaired fR response to hypercapnia in PD animals with depletion of orexinergic neurons in awake and sleeping rats. In conclusion, the degeneration of orexinergic neurons in this model of PD can be related to impaired chemoreceptor function in the dark phase.

Direct and indirect nigrofugal projections to the nucleus reticularis pontis caudalis mediate in the motor execution of the acoustic startle reflex.

The acoustic startle reflex (ASR) is a short and intense defensive reaction in response to a loud and unexpected acoustic stimulus. In the rat, a primary startle pathway encompasses three serially connected central structures: the cochlear root neurons, the giant neurons of the nucleus reticularis pontis caudalis (PnC), and the spinal motoneurons. As a sensorimotor interface, the PnC has a central role in the ASR circuitry, especially the integration of different sensory stimuli and brain states into initiation of motor responses. Since the basal ganglia circuits control movement and action selection, we hypothesize that their output via the substantia nigra (SN) may interplay with the ASR primary circuit by providing inputs to PnC. Moreover, the pedunculopontine tegmental nucleus (PPTg) has been proposed as a functional and neural extension of the SN, so it is another goal of this study to describe possible anatomical connections from the PPTg to PnC. Here, we made 6-OHDA neurotoxic lesions of the SN pars compacta (SNc) and submitted the rats to a custom-built ASR measurement session to assess amplitude and latency of motor responses. We found that following lesion of the SNc, ASR amplitude decreased and latency increased compared to those values from the sham-surgery and control groups. The number of dopamine neurons remaining in the SNc after lesion was also estimated using a stereological approach, and it correlated with our behavioral results. Moreover, we employed neural tract-tracing techniques to highlight direct projections from the SN to PnC, and indirect projections through the PPTg. Finally, we also measured levels of excitatory amino acid neurotransmitters in the PnC following lesion of the SN, and found that they change following an ipsi/contralateral pattern. Taken together, our results identify nigrofugal efferents onto the primary ASR circuit that may modulate motor responses.

Early sensory experience influences the development of multisensory thalamocortical and intracortical connections of primary sensory cortices.

The nervous system integrates information from multiple senses. This multisensory integration already occurs in primary sensory cortices via direct thalamocortical and corticocortical connections across modalities. In humans, sensory loss from birth results in functional recruitment of the deprived cortical territory by the spared senses but the underlying circuit changes are not well known. Using tracer injections into primary auditory, somatosensory, and visual cortex within the first postnatal month of life in a rodent model (Mongolian gerbil) we show that multisensory thalamocortical connections emerge before corticocortical connections but mostly disappear during development. Early auditory, somatosensory, or visual deprivation increases multisensory connections via axonal reorganization processes mediated by non-lemniscal thalamic nuclei and the primary areas themselves. Functional single-photon emission computed tomography of regional cerebral blood flow reveals altered stimulus-induced activity and higher functional connectivity specifically between primary areas in deprived animals. Together, we show that intracortical multisensory connections are formed as a consequence of sensory-driven multisensory thalamocortical activity and that spared senses functionally recruit deprived cortical areas by an altered development of sensory thalamocortical and corticocortical connections. The functional-anatomical changes after early sensory deprivation have translational implications for the therapy of developmental hearing loss, blindness, and sensory paralysis and might also underlie developmental synesthesia.

Neuronal aromatase expression in pain processing regions of the medullary and spinal cord dorsal horn.

In both acute and chronic pain conditions, women tend to be more sensitive than men. This sex difference may be regulated by estrogens, such as estradiol, that are synthesized in the spinal cord and brainstem and act locally to influence pain processing. To identify a potential cellular source of local estrogen, here we examined the expression of aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol. Our studies focused on primary afferent neurons and on their central targets in the spinal cord and medulla as well as in the nucleus of the solitary tract, the target of nodose ganglion-derived visceral afferents. Immunohistochemical staining in an aromatase reporter mouse revealed that many neurons in laminae I and V of the spinal cord dorsal horn and caudal spinal trigeminal nucleus and in the nucleus of the solitary tract express aromatase. The great majority of these cells also express inhibitory interneuron markers. We did not find sex differences in aromatase expression and neither the pattern nor the number of neurons changed in a sciatic nerve transection model of neuropathic pain or in the Complete Freund's adjuvant model of inflammatory pain. A few aromatase neurons express Fos after cheek injection of capsaicin, formalin, or chloroquine. In total, given their location, these aromatase neurons are poised to engage nociceptive circuits, whether it is through local estrogen synthesis or inhibitory neurotransmitter release.

Thalamic and Entorhinal Network Activity Differently Modulates the Functional Development of Prefrontal-Hippocampal Interactions.

Precise information flow during mnemonic and executive tasks requires the coactivation of adult prefrontal and hippocampal networks in oscillatory rhythms. This interplay emerges early in life, most likely as an anticipatory template of later cognitive performance. At neonatal age, hippocampal theta bursts drive the generation of prefrontal theta-gamma oscillations. In the absence of direct reciprocal interactions, the question arises of which feedback mechanisms control the early entrainment of prefrontal-hippocampal networks. Here, we demonstrate that prefrontal-hippocampal activity couples with discontinuous theta oscillations and neuronal firing in both lateral entorhinal cortex and ventral midline thalamic nuclei of neonatal rats. However, these two brain areas have different contributions to the neonatal long-range communication. The entorhinal cortex mainly modulates the hippocampal activity via direct axonal projections. In contrast, thalamic theta bursts are controlled by the prefrontal cortex via mutual projections and contribute to hippocampal activity. Thus, the neonatal prefrontal cortex modulates the level of hippocampal activation by directed interactions with the ventral midline thalamus. Similar to the adult task-related communication, theta-band activity ensures the feedback control of long-range coupling in the developing brain. SIGNIFICANCE STATEMENT: Memories are encoded by finely tuned interactions within large-scale neuronal networks. This cognitive performance is not inherited, but progressively matures in relationship with the establishment of long-range coupling in the immature brain. The hippocampus initiates and unidirectionally drives the oscillatory entrainment of neonatal prefrontal cortex, yet feedback interactions that precisely control this early communication are still unresolved. Here, we identified distinct roles of entorhinal cortex and ventral midline thalamus for the functional development of prefrontal-hippocampal interactions. While entorhinal oscillations modulate the hippocampal activity by timing the neuronal firing via monosynaptic afferents, thalamic nuclei act as a relay station routing prefrontal activation back to hippocampus. Understanding the mechanisms of network maturation represents the prerequisite for assessing circuit dysfunction in neurodevelopmental disorders.

Nonspecific labeling limits the utility of Cre-Lox bred CST-YFP mice for studies of corticospinal tract regeneration.

Studies of axon regeneration in the spinal cord often assess regeneration of the corticospinal tract (CST). Emx1-Cre x Thy1-STOP-YFP mice have been reported to have yellow fluorescent protein (YFP) selectively expressed in forebrain neurons leading to genetic labeling of CST axons in the spinal cord, and it was suggested that these CST-YFP mice would be useful for studies of CST regeneration. Because regeneration past a lesion may involve only a few axons, the presence of labeled non-CST axons compromises interpretation. We show here that in CST-YFP mice, some YFP-labeled axons are not from the CST. Specifically, YFP-labeled axons are present in regions beyond those with anterogradely labeled CST axons, most YFP-labeled axons beyond established CST locations do not undergo Wallerian degeneration following a large lesion of the sensorimotor cortex, some rubrospinal and reticulospinal neurons are labeled with YFP, and some YFP-labeled cells in the spinal gray matter have YFP-labeled projections into the spinal cord white matter. We further demonstrate that the density of YFP-labeled axon arbors hinders tracing of single axons to their point of origin in the main descending tracts. In light of recent advances in 3D imaging for visualizing axons in unsectioned blocks of spinal cord, we also assessed CST-YFP mice for 3D imaging and found that YFP fluorescence in CST-YFP mice is faint for clearing-based 3D imaging in comparison with fluorescence in Thy1-YFP-H mice and fluorescence of mini-ruby biotinylated dextran amine (BDA). Overall, the nonspecific and faint YFP labeling in CST-YFP mice limits their utility for assessments of CST axon regeneration.

The dorsal tectal longitudinal column (TLCd): a second longitudinal column in the paramedian region of the midbrain tectum.

The tectal longitudinal column (TLC) is a longitudinally oriented, long and narrow nucleus that spans the paramedian region of the midbrain tectum of a large variety of mammals (Saldaña et al. in J Neurosci 27:13108-13116, 2007). Recent analysis of the organization of this region revealed another novel nucleus located immediately dorsal, and parallel, to the TLC. Because the name "tectal longitudinal column" also seems appropriate for this novel nucleus, we suggest the TLC described in 2007 be renamed the "ventral tectal longitudinal column (TLCv)", and the newly discovered nucleus termed the "dorsal tectal longitudinal column (TLCd)". This work represents the first characterization of the rat TLCd. A constellation of anatomical techniques was used to demonstrate that the TLCd differs from its surrounding structures (TLCv and superior colliculus) cytoarchitecturally, myeloarchitecturally, neurochemically and hodologically. The distinct expression of vesicular amino acid transporters suggests that TLCd neurons are GABAergic. The TLCd receives major projections from various areas of the cerebral cortex (secondary visual mediomedial area, and granular and dysgranular retrosplenial cortices) and from the medial pretectal nucleus. It densely innervates the ipsilateral lateral posterior and laterodorsal nuclei of the thalamus. Thus, the TLCd is connected with vision-related neural centers. The TLCd may be unique as it constitutes the only known nucleus made of GABAergic neurons dedicated to providing massive inhibition to higher order thalamic nuclei of a specific sensory modality.

Differential expression of VGLUT1 or VGLUT2 in the trigeminothalamic or trigeminocerebellar projection neurons in the rat.

The vesicular glutamate transporters, VGLUT1 and VGLUT2, reportedly display complementary distribution in the rat brain. However, co-expression of them in single neurons has been reported in some brain areas. We previously found co-expression of VGLUT1 and VGLUT2 mRNAs in a number of single neurons in the principal sensory trigeminal nucleus (Vp) of the adult rat; the majority of these neurons sent their axons to the thalamic regions around the posteromedial ventral nucleus (VPM) and the posterior nuclei (Po). It is well known that trigeminothalamic (T-T) projection fibers arise not only from the Vp but also from the spinal trigeminal nucleus (Vsp), and that trigeminocerebellar (T-C) projection fibers take their origins from both of the Vp and Vsp. Thus, in the present study, we examined the expression of VGLUT1 and VGLUT2 in Vp and Vsp neurons that sent their axons to the VPM/Po regions or the cortical regions of the cerebellum. For this purpose, we combined fluorescence in situ hybridization (FISH) histochemistry with retrograde tract-tracing; immunofluorescence histochemistry was also combined with anterograde tract-tracing. The results indicate that glutamatergic Vsp neurons sending their axons to the cerebellar cortical regions mainly express VGLUT1, whereas glutamatergic Vsp neurons sending their axons to the thalamic regions express VGLUT2. The present data, in combination with those of our previous study, indicate that glutamatergic Vp neurons projecting to the cerebellar cortical regions express mainly VGLUT1, whereas the majority of glutamatergic Vp neurons projecting to the thalamus co-express VGLUT1 and VGLUT2.

Musculotopic organization of the motor neurons supplying the mouse hindlimb muscles: a quantitative study using Fluoro-Gold retrograde tracing.

We have mapped the motor neurons (MNs) supplying the major hindlimb muscles of transgenic (C57/BL6J-ChAT-EGFP) and wild-type (C57/BL6J) mice. The fluorescent retrograde tracer Fluoro-Gold was injected into 19 hindlimb muscles. Consecutive transverse spinal cord sections were harvested, the MNs counted, and the MN columns reconstructed in 3D. Three longitudinal MN columns were identified. The dorsolateral column extends from L4 to L6 and consists of MNs innervating the crural muscles and the foot. The ventrolateral column extends from L1 to L6 and accommodates MNs supplying the iliopsoas, gluteal, and quadriceps femoris muscles. The middle part of the ventral horn hosts the central MN column, which extends between L2 and L6 and consists of MNs for the thigh adductor, hamstring, and quadratus femoris muscles. Within these longitudinal columns, the arrangement of the different MN groups reflects their somatotopic organization. MNs innervating muscles developing from the dorsal (e.g., quadriceps) and ventral muscle mass (e.g., hamstring) are situated in the lateral and medial part of the ventral gray, respectively. MN pools belonging to proximal muscles (e.g., quadratus femoris and iliopsoas) are situated ventral to those supplying more distal ones (e.g., plantar muscles). Finally, MNs innervating flexors (e.g., posterior crural muscles) are more medial than those belonging to extensors of the same joint (e.g., anterior crural muscles). These data extend and modify the MN maps in the recently published atlas of the mouse spinal cord and may help when assessing neuronal loss associated with MN diseases.

Seasonal changes in RFamide-related peptide-3 neurons in the hypothalamus of a seasonally breeding marsupial species, the brushtail possum (Trichosurus vulpecula).

RFamide-related peptide-3 (RFRP-3) neurons have been shown to inhibit gonadotropin-releasing hormone (GnRH) neuronal activity and hence reproduction in birds and eutherian mammals. They have also been proposed to have a direct hypophysiotropic effect on pituitary gonadotropin release. We used a new RFRP-3 antibody to characterize the cell body distribution and fiber projections of RFRP-3 neurons in the adult female brushtail possum brain. RFRP-3-immunoreactive cell bodies were found scattered within the dorsomedial hypothalamus and the dorsomedial half of the ventromedial hypothalamus, while GnRH neurons were observed scattered rostrocaudally along the lateral septum, rostral to the medial septum. There was a significant 2-fold increase in the RFRP-3 cell body number during the nonbreeding season (summer) compared to the breeding season (winter). Immunoreactive RFRP-3 fibers were distributed throughout the thalamus, preoptic area, and hypothalamus. Very few fibers were observed in the median eminence, especially in the external zone. Intraperitoneal injection of the retrograde tracer Fluoro-Gold resulted in the labeling of 40% of hypophysiotropic tuberoinfundibular dopaminergic (tyrosine hydroxylase-positive) neurons; however, <10% of zona incerta dopaminergic neurons (which are not hypophysiotropic) or RFRP-3 neurons were labeled with this tracer. These observations suggest that RFRP-3 exhibits a seasonal fluctuation in cell numbers, as seen in sheep and birds, which is consistent with an increased inhibitory tone during the nonbreeding season. The lack of RFRP-3 fibers in the median eminence and of Fluoro-Gold uptake from the periphery imply that the actions of this peptide occur primarily centrally rather than at the anterior pituitary gland.

On lateral septum-like characteristics of outputs from the accumbal hedonic "hotspot" of Peciña and Berridge with commentary on the transitional nature of basal forebrain "boundaries".

Peciña and Berridge (2005; J Neurosci 25:11777-11786) observed that an injection of the µ-opioid receptor agonist DAMGO (D-ala(2) -N-Me-Phe(4) -Glycol(5) -enkephalin) into the rostrodorsal part of the accumbens shell (rdAcbSh) enhances expression of hedonic "liking" responses to the taste of an appetitive sucrose solution. Insofar as the connections of this hedonic "hotspot" were not singled out for special attention in the earlier neuroanatomical literature, we undertook to examine them. We observed that the patterns of inputs and outputs of the rdAcbSh are not qualitatively different from those of the rest of the Acb, except that outputs from the rdAcbSh to the lateral preoptic area and anterior and lateral hypothalamic areas are anomalously robust and overlap extensively with those of the lateral septum. We also detected reciprocal interconnections between the rdAcbSh and lateral septum. Whether and how these connections subserve hedonic impact remains to be learned, but these observations lead us to hypothesize that the rdAcbSh represents a basal forebrain transition area, in the sense that it is invaded by neurons of the lateral septum, or possibly transitional neuronal forms sharing properties of both structures. We note that the proposed transition zone between lateral septum and rdAcbSh would be but one of many in the basal forebrain and conclude by reiterating the longstanding argument that the transitional nature of such boundary areas has functional importance, of which the precise nature will remain elusive until the neurophysiological and neuropharmacological implications of such zones of transition are more generally acknowledged and better addressed.

Hypothalamic and other connections with dorsal CA2 area of the mouse hippocampus.

The CA2 area is an important, although relatively unexplored, component of the hippocampus. We used various tracers to provide a comprehensive analysis of CA2 connections in C57BL/6J mice. Using various adeno-associated viruses that express fluorescent proteins, we found a vasopressinergic projection from the paraventricular nuclei of the hypothalamus (PVN) to the CA2 as well as a projection from pyramidal neurons of the CA2 to the supramammillary nuclei. These projections were confirmed by retrograde tracing. As expected, we observed CA2 afferent projections from neurons in ipsilateral entorhinal cortical layer II as well as from bilateral dorsal CA2 and CA3 using retrograde tracers. Additionally, we saw CA2 neuronal input from bilateral medial septal nuclei, vertical and horizontal limbs of the nucleus of diagonal band of Broca, supramammillary nuclei (SUM), and median raphe nucleus. Dorsal CA2 injections of adeno-associated virus expressing green fluorescent protein revealed axonal projections primarily to dorsal CA1, CA2, and CA3 bilaterally. No projection was detected to the entorhinal cortex from the dorsal CA2. These results are consistent with recent observations that the dorsal CA2 forms disynaptic connections with the entorhinal cortex to influence dynamic memory processing. Mouse dorsal CA2 neurons send bilateral projections to the medial and lateral septal nuclei, vertical and horizontal limbs of the diagonal band of Broca, and SUM. Novel connections from the PVN and to the SUM suggest important regulatory roles for CA2 in mediating social and emotional input for memory processing.

Purinergic modulation of neuronal activity in developing auditory brainstem.

In the developing nervous system, spontaneous neuronal activity arises independently of experience or any environmental input. This activity may play a major role in axonal pathfinding, refinement of topographic maps, dendritic morphogenesis, and the segregation of axonal terminal arbors. In the auditory system, endogenously released ATP in the cochlea activates inner hair cells to trigger bursts of action potentials (APs), which are transferred to the central auditory system. Here we show the modulatory role of purinergic signaling beyond the cochlea, i.e., the developmentally regulated and cell-type-specific depolarizing effects on auditory brainstem neurons of Mongolian gerbil. We assessed the effects of P2X receptors (P2XRs) on neuronal excitability from prehearing to early stages of auditory signal processing. Our results demonstrate that in neurons expressing P2XRs, extracellular ATP can evoke APs in sync with Ca(2+) signals. In cochlear nucleus (CN) bushy cells, ATP increases spontaneous and also acoustically evoked activity in vivo, but these effects diminish with maturity. Moreover, ATP not only augmented glutamate-driven firing, but it also evoked APs in the absence of glutamatergic transmission. In vivo recordings also revealed that endogenously released ATP in the CN contributes to neuronal firing activity by facilitating AP generation and prolonging AP duration. Given the enhancing effect of ATP on AP firing and confinement of P2XRs to certain auditory brainstem nuclei, and to distinct neurons within these nuclei, it is conceivable that purinergic signaling plays a specific role in the development of neuronal brainstem circuits.

Thalamic POm projections to the dorsolateral striatum of rats: potential pathway for mediating stimulus-response associations for sensorimotor habits.

The dorsolateral part of the striatum (DLS) represents the initial stage for processing sensorimotor information in the basal ganglia. Although the DLS receives much of its input from the primary somatosensory (SI) cortex, peripheral somesthetic stimulation activates the DLS at latencies that are shorter than the response latencies recorded in the SI cortex. To identify the subcortical regions that transmit somesthetic information directly to the DLS, we deposited small quantities of retrograde tracers at DLS sites that displayed consistent time-locked responses to controlled whisker stimulation. The neurons that were retrogradely labeled by these injections were located mainly in the sensorimotor cortex and, to a lesser degree, in the amygdala and thalamus. Quantitative analysis of neuronal labeling in the thalamus indicated that the strongest thalamic input to the whisker-sensitive part of the DLS originates from the medial posterior nucleus (POm), a somesthetic-related region that receives inputs from the spinal trigeminal nucleus. Anterograde tracer injections in POm confirmed that this thalamic region projects to the DLS neuropil. In subsequent experiments, simultaneous recordings from POm and the DLS during whisker stimulation showed that POm consistently responds before the DLS. These results suggest that POm could transmit somesthetic information to the DLS, and this modality-specific thalamostriatal pathway may cooperate with the thalamostriatal projections that originate from the intralaminar nuclei.

Sonic hedgehog expression in corticofugal projection neurons directs cortical microcircuit formation.

VIDEO ABSTRACT: The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry.

Regulation of hypothalamic signaling by tuberoinfundibular peptide of 39 residues is critical for the response to cold: a novel peptidergic mechanism of thermoregulation.

Euthermia is critical for mammalian homeostasis. Circuits within the preoptic hypothalamus regulate temperature, with fine control exerted via descending GABAergic inhibition of presympathetic motor neurons that control brown adipose tissue (BAT) thermogenesis and cutaneous vascular tone. The thermoregulatory role of hypothalamic excitatory neurons is less clear. Here we report peptidergic regulation of preoptic glutamatergic neurons that contributes to temperature regulation. Tuberoinfundibular peptide of 39 residues (TIP39) is a ligand for the parathyroid hormone 2 receptor (PTH2R). Both peptide and receptor are abundant in the preoptic hypothalamus. Based on PTH2R and vesicular glutamate transporter 2 (VGlut2) immunolabeling in animals with retrograde tracer injection, PTH2R-containing glutamatergic fibers are presynaptic to neurons projecting from the median preoptic nucleus (MnPO) to the dorsomedial hypothalamus. Transneuronal retrograde pathway tracing with pseudorabies virus revealed connectivity between MnPO VGlut2 and PTH2R neurons and BAT. MnPO injection of TIP39 increased body temperature by 2°C for several hours. Mice lacking TIP39 signaling, either because of PTH2R-null mutation or brain delivery of a PTH2R antagonist had impaired heat production upon cold exposure, but no change in basal temperature and no impairment in response to a hot environment. Thus, TIP39 appears to act on PTH2Rs present on MnPO glutamatergic terminals to regulate their activation of projection neurons and subsequent sympathetic BAT activation. This excitatory mechanism of heat production appears to be activated on demand, during cold exposure, and parallels the tonic inhibitory GABAergic control of body temperature.

The sound of silence: ionic mechanisms encoding sound termination.

Offset responses upon termination of a stimulus are crucial for perceptual grouping and gap detection. These gaps are key features of vocal communication, but an ionic mechanism capable of generating fast offsets from auditory stimuli has proven elusive. Offset firing arises in the brainstem superior paraolivary nucleus (SPN), which receives powerful inhibition during sound and converts this into precise action potential (AP) firing upon sound termination. Whole-cell patch recording in vitro showed that offset firing was triggered by IPSPs rather than EPSPs. We show that AP firing can emerge from inhibition through integration of large IPSPs, driven by an extremely negative chloride reversal potential (E(Cl)), combined with a large hyperpolarization-activated nonspecific cationic current (I(H)), with a secondary contribution from a T-type calcium conductance (I(TCa)). On activation by the IPSP, I(H) potently accelerates the membrane time constant, so when the sound ceases, a rapid repolarization triggers multiple offset APs that match onset timing accuracy.

Quantitative analysis of spinothalamic tract neurons in adult and developing mouse.

Understanding the development of nociceptive circuits is important for the proper treatment of pain and administration of anesthesia to prenatal, newborn, and infant organisms. The spinothalamic tract (STT) is an integral pathway in the transmission of nociceptive information to the brain, yet the stage of development when axons from cells in the spinal cord reach the thalamus is unknown. Therefore, the retrograde tracer Fluoro-Gold was used to characterize the STT at several stages of development in the mouse, a species in which the STT was previously unexamined. One-week-old, 2-day-old and embryonic-day-18 mice did not differ from adults in the number or distribution of retrogradely labeled STT neurons. Approximately 3,500 neurons were retrogradely labeled from one side of the thalamus in each age group. Eighty percent of the labeled cells were located on the side of the spinal cord contralateral to the injection site. Sixty-three percent of all labeled cells were located within the cervical cord, 18% in thoracic cord, and 19% in the lumbosacral spinal cord. Retrogradely labeled cells significantly increased in diameter over the first postnatal week. Arborizations and boutons within the ventrobasal complex of the thalamus were observed after the anterograde tracer biotinylated dextran amine was injected into the neonatal spinal cord. These data indicate that, whereas neurons of the STT continue to increase in size during the postnatal period, their axons reach the thalamus before birth and possess some of the morphological features required for functionality.

Angelica injection improves functional recovery and motoneuron maintenance with increased expression of brain derived neurotrophic factor and nerve growth factor.

This study assessed the neuroprotective effects of angelica injection in the rat sciatic nerve crush injury (SCI). Forty eight male Sprague Dawley rats were randomly divided into 4 groups: one was the sham group (S), which received sham surgery and given saline injection and the others were received SCI surgery and given saline injection, high and low dose angelica injection for 4 weeks, respectively. The sciatic functional index (SFI) in walking-track analysis, conductive velocity (CV), the number of fluorogold labeled motoneurons, and the expression patterns of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the sciatic nerve and spine were examined. The results showed that SFI descended gradually on day 7, and dropped more quickly on day 28 in treatment groups (Low and High dose group). The CV in treatment groups was higher than control group (C). The numbers of motoneurons in treatment groups were larger than C group (P<0.05), but less than that in S group (P<0.01). The expressions of BDNF and NGF protein in the groups received SCI surgery were significantly lower than in S group, but the protein expressions in the groups received angelica injections were significantly higher than that in C group (P<0.01). These findings suggested that angelica injection can improve the sciatic nerve crush injury, and the mechanism might be through the increase of BDNF and NGF protein expression.

Localization of prolyl oligopeptidase in the thalamic and cortical projection neurons: a retrograde neurotracing study in the rat brain.

Prolyl oligopeptidase (POP) is a serine endopeptidase which hydrolyses proline-containing peptides shorter than 30-mer. POP is believed to be associated with cognitive functions via neuropeptide cleavage. POP has been also connected to the inositol 1,4,5-triphosphate (IP(3)) signalling but the effects of POP-inhibition to the IP(3) accumulation in vivo are still unclear. However, little is known about the physiological role of POP in the brain. We have previously found that in the rat brain POP was specifically expressed in the pyramidal neurons of the cerebral cortex, particularly in the primary motor and somatosensory cortices, and corresponding projection areas in thalamus. Using a retrograde neurotracer we have now visualized the localization of POP in thalamocortical and corticothalamic projection neurons in ventrobasal complex and medial geniculate nucleus of thalamus and somatosensory/motor and auditory cortices. We observed that both in thalamus and cortex over 50% of projection neurons contained POP. These results support the hypothesis that POP is involved in thalamocortical and corticothalamic signal processing. We also propose, based on our neuroanatomical findings and literature, that POP may take part in the thalamocortical oscillations by interacting with IP(3) signalling in cells.