DEVELOPMENT OF FERRET SOMATOROLE OF ACTIVITY IN THE DEVELOPMENT SENSORY CORTEX IN NORMAL AND LAYERAND MAINTENANCE OF THALAMOCORTICAL DELETED ANIMALS IN VW0 AND IN v7TRO. AND INTRACORTICAL CONNECTIONS IN THE RAT’S PRIMARY SOMATOSENSORY CORTEX S.L. Juliano, S.L. Palmer, S.C. Noctor. Department of Anatomy & Cell Biology, Program in Neuroscience, USUHS. Bethesda, MD 20895, USA. Robert W. Rhoades, Nicolas L. Chiaia and Carol Bennett-Clarke Dept. Anat. Neurobiol., Med. College of Ohio, Toledo, OH, USA

The current study examined the neurochemical mechanisms and neuroanatomical changes underlying coexisting behavioral effects associated with chronic-stress-induced alterations in serotonin (5HT) neurons. Chronic unpredictable stress (CUS) to adult male rats produced depression-like changes with cognitive dysfunction and selective cell death in the interfascicular nucleus of the dorsal raphe (DRif), resulting in decreased 5HTergic innervation of medial prefrontal cortex (mPFC). Twenty-one days of CUS decreased basal plasma levels of corticosterone and produced a shorter latency to immobility and longer durations of immobility in the force-swim test that persisted for 1 month after CUS. Deficits in acquisition, recall, perseveration, and reversal learning were evident 1 month after CUS. MK801 treatment during CUS blocked the changes in the forced-swim test and deficits in memory recall. These behavioral changes were associated with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive soma and the eventual loss of 5HT neurons in the DRif and its projections to the mPFC as evidenced by fewer labeled cells in the DRif after retrograde tracer injections into the mPFC of stressed rats. Similar to the effects of MK801 on behavior, MK801 pretreatment during stress blocked the CUS-induced decreases in 5HT soma within the DRif and its projections to the mPFC. Finally, the depression-like behaviors were blocked by acute injection of the 5HT2A/C agonist (−)-2,5-dimethoxy-4-iodoamphetamine hydrochloride into the mPFC before forced-swim testing. These results identify a cause and mechanism of 5HTergic dysfunction of the mPFC and associated mood and cognitive behaviors. SIGNIFICANCE STATEMENT Chronic stress causes persistent mood and cognitive changes typically associated with dysregulated serotonin (5HT) transmission in the medial prefrontal cortex (mPFC), but the cause of this dysregulation is unknown. Prior studies have focused on 5HTergic terminals in this region, but this study shows that chronic stress causes NMDA-receptor-dependent and subregion-specific cell death of 5HT neurons in the dorsal raphe. The consequent decreased 5HT innervation of the mPFC was associated with mood and cognitive changes that persisted long after the termination of stress. These findings identify a mechanism of subregion-selective death of 5HT neurons in the dorsal raphe, a defined neuroanatomical pathway, and a behavioral phenotype that mirror stress-associated diseases such as major depressive disorder.

3,4-methylenedioxymethamphetamine (MDMA) is a widely abused psychostimulant, which causes release of serotonin in various forebrain regions. Recently, we reported that MDMA increases extracellular glutamate concentrations in the dentate gyrus, via activation of 5HT2A receptors. We examined the role of prostaglandin signaling in mediating the effects of 5HT2A receptor activation on the increases in extracellular glutamate and the subsequent long-term loss of parvalbumin interneurons in the dentate gyrus caused by MDMA. Administration of MDMA into the dentate gyrus of rats increased PGE2 concentrations which was prevented by coadministration of MDL100907, a 5HT2A receptor antagonist. MDMA-induced increases in extracellular glutamate were inhibited by local administration of SC-51089, an inhibitor of the EP1 prostaglandin receptor. Systemic administration of SC-51089 during injections of MDMA prevented the decreases in parvalbumin interneurons observed 10 days later. The loss of parvalbumin immunoreactivity after MDMA exposure coincided with a decrease in paired-pulse inhibition and afterdischarge threshold in the dentate gyrus. These changes were prevented by inhibition of EP1 and 5HT2A receptors during MDMA. Additional experiments revealed an increased susceptibility to kainic acid-induced seizures in MDMA-treated rats, which could be prevented with SC51089 treatments during MDMA exposure. Overall, these findings suggest that 5HT2A receptors mediate MDMA-induced PGE2 signaling and subsequent increases in glutamate. This signaling mediates parvalbumin cell losses as well as physiologic changes in the dentate gyrus, suggesting that the lack of the inhibition provided by these neurons increases the excitability within the dentate gyrus of MDMA-treated rats. We hypothesized that the widely abused psychostimulant MDMA causes a loss of parvalbumin (PV) cells and increases excitability in the dentate gyrus. MDMA increases serotonin (5HT) release and activates 5HT2A receptors. The increased activation of 5HT2A receptors promotes the production of prostaglandin E2 (PGE2) and subsequent activation of EP1 receptors in the dentate gyrus. EP1 receptor activation leads to eventual excitotoxicity and loss of PV interneurons resulting in reduced inhibition and lowered seizure threshold resulting in increased seizure susceptibility.

An enormous amount of efforts have been poured to find an effective therapeutic agent for the treatment of neurodegenerative diseases including Alzheimer's disease (AD). Among those, neurotrophic peptides that regenerate neuronal structures and increase neuron survival show a promise in slowing neurodegeneration. However, the short plasma half-life and poor blood-brain-barrier (BBB)-permeability of neurotrophic peptides limit their in vivo efficacy. Thus, an alternative neurotrophic agent that has longer plasma half-life and better BBB-permeability has been sought for. Based on the recent findings of neuroprotective polysaccharides, we searched for a BBB-permeable neuroprotective polysaccharide among natural polysaccharides that are approved for human use. Then, we discovered midi-GAGR, a BBB-permeable, long plasma half-life, strong neuroprotective and neurotrophic polysaccharide. Midi-GAGR is a 4.7kD cleavage product of low acyl gellan gum that is approved by FDA for human use. Midi-GAGR protected rodent cortical neurons not only from the pathological concentrations of co-/post-treated free reactive radicals and Aβ42 peptide but also from activated microglial cells. Moreover, midi-GAGR showed a good neurotrophic effect; it enhanced neurite outgrowth and increased phosphorylated cAMP-responsive element binding protein (pCREB) in the nuclei of primary cortical neurons. Furthermore, intra-nasally administered midi-GAGR penetrated the BBB and exerted its neurotrophic effect inside the brain for 24 h after one-time administration. Midi-GAGR appears to activate fibroblast growth factor receptor 1 (FGFR1) and its downstream neurotrophic signaling pathway for neuroprotection and CREB activation. Additionally, 14-day intranasal administration of midi-GAGR not only increased neuronal activity markers but also decreased hyperphosphorylated tau, a precursor of neurofibrillary tangle, in the brains of the AD mouse model, 3xTg-AD. Taken together, midi-GAGR with good BBB-permeability, long plasma half-life, and strong neuroprotective and neurotrophic effects has a great therapeutic potential for the treatment of neurodegenerative diseases, especially AD.

Recently, some polysaccharides showed therapeutic potentials for the treatment of neurodegenerative diseases while the most important property, their permeability to the blood brain barrier (BBB) that sheathes the brain and spinal cord, is not yet determined. The determination has been delayed by the difficulty in tracking a target polysaccharide among endogenous polysaccharides in animal. We developed an easy way to examine the BBB-permeability and, possibly, tissue distribution of a target polysaccharide in animal. We tagged a polysaccharide with fluorescent 8-aminonaphthalene-1,3,6-trisulfonic acid disodium salt (ANTS) for tracking. We also developed a simple method to separate ANTS-tagged polysaccharide from unconjugated free ANTS using 75% ethanol. After ANTS-polysaccharide was intra-nasally administered into animals, we could quantify the amounts of ANTS-polysaccharide in the brain and the serum by fluorocytometry. We could also separate free ANTS-polysaccharide from serum proteins using trichloroacetic acid (TCA) and 75% ethanol. Our method will help to track a polysaccharide in animal easily. ANTS-labeling is less tedious than but as powerful as radiolabeling for tracking a target polysaccharide in animal.Our simple method can separate structurally intact ANTS-polysaccharide from animal serum and tissues.This method is good for the fluorometry-based measurement of ANTS-conjugated macromolecules in tissues.

The extensive invasive capacity of glioblastoma (GBM) makes it resistant to surgery, radiotherapy, and chemotherapy and thus makes it lethal. In vivo, GBM invasion is mediated by Rho GTPases through unidentified downstream effectors. Mammalian Diaphanous (mDia) family formins are Rho-directed effectors that regulate the F-actin cytoskeleton to support tumor cell motility. Historically, anti-invasion strategies focused upon mDia inhibition, whereas activation remained unexplored. The recent development of small molecules directly inhibiting or activating mDia-driven F-actin assembly that supports motility allows for exploration of their role in GBM. We used the formin inhibitor SMIFH2 and mDia agonists IMM-01/-02 and mDia2-DAD peptides, which disrupt autoinhibition, to examine the roles of mDia inactivation versus activation in GBM cell migration and invasion in vitro and in an ex vivo brain slice invasion model. Inhibiting mDia suppressed directional migration and spheroid invasion while preserving intrinsic random migration. mDia agonism abrogated both random intrinsic and directional migration and halted U87 spheroid invasion in ex vivo brain slices. Thus mDia agonism is a superior GBM anti-invasion strategy. We conclude that formin agonism impedes the most dangerous GBM component-tumor spread into surrounding healthy tissue. Formin activation impairs novel aspects of transformed cells and informs the development of anti-GBM invasion strategies.

Several Eph receptors, prominently EphA4 and EphA7, and their corresponding ligands are known to influence neocortical development, including topographic sorting of thalamocortical axons within primary somatosensory cortex (SI). This study investigated postnatal expression of a ligand that can bind to these receptors, ephrin‐A2. Quantitative methods revealed that expression of ephrin‐A2 mRNA in SI reached maximum levels on postnatal day (P) 4 and dropped thereafter to background by P18. Ephrin‐A2 mRNA expression assessed by in situ hybridization qualitatively revealed a similar time course and localized the expression pattern primarily in two broad laminae in SI, comprising the supragranular and infragranular layers, and with additional expression in the subplate. This expression pattern was investigated in greater detail using immunohistochemistry for ephrin‐A2 protein. Immunoreactivity generally showed the same laminar distribution as seen with in situ hybridization, except that it persisted longer, lasting to approximately P14. Expression in the cortical plate was low or absent within presumptive layer IV, and it remained so as cortical lamination progressed. Double‐labeling immunohistochemistry with confocal microscopy revealed that cortical neurons were the principal elements expressing ephrin‐A2 protein. These findings are consistent with possible involvement of ephrin‐A2, in concert with one or more Eph receptors, in influencing arbor development of thalamocortical axons at cortical layer IV boundaries. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.

Magnetic resonance imaging (MRI) was used to evaluate within-subject variability in global mean cortical thickness over test-retest intervals of minutes-weeks in five healthy adults. Within-subject measures of global mean thickness were consistent over these intervals. Test-retest assessments of absolute thickness differences and percent thickness differences indicated variations of, respectively, < or =0.05-0.06 mm and < or =+/-1.9-2.3%. There have been few evaluations of normal within-subject variations in cortical thickness. The present results suggest that within-subject variability in global mean cortical thickness can be low over test-retest intervals of minutes-weeks, and that longitudinal scans can establish useful baseline estimates of variability from which to assess changes due to injury, disease, or other experiences.

Neonatal forelimb amputation in rats produces sprouting of sciatic nerve afferent fibers into the cuneate nucleus (CN) and results in 40% of individual CN neurons expressing both forelimb-stump and hindlimb receptive fields. The forelimb-stump region of primary somatosensory cortex (S-I) of these rats contains neurons in layer IV that express both stump and hindlimb receptive fields. However, the source of the aberrant input is the S-I hindlimb region conveyed to the S-I forelimb-stump region via intracortical projections. Although the reorganization in S-I reflects changes in cortical circuitry, it is possible that these in turn are dependent on the CN reorganization. The present study was designed to directly test whether the sprouting of sciatic afferents into the CN is required for expression of the hindlimb inputs in the S-I forelimb-stump field. To inhibit sprouting, neurotrophin-3 (NT-3) was applied to the cut nerves following amputation. At P60 or older, NT-3-treated rats showed minimal sciatic nerve fibers in the CN. Multiunit electrophysiological recordings in the CN of NT-3-treated, amputated rats revealed 6.3% of sites were both stump/hindlimb responsive, compared with 30.5% in saline-treated amputated animals. Evaluation of the S-I following GABA receptor blockade, revealed that the percentage of hindlimb responsive sites in the stump representation of the NT-3-treated rats (34.2%) was not significantly different from that in saline-treated rats (31.5%). These results indicate that brain stem reorganization in the form of sprouting of sciatic afferents into the CN is not necessary for development of anomalous hindlimb receptive fields within the S-I forelimb/stump region.

In neonatal rodents, elevated levels of cortical serotonin (5-HT) blur the normally segmented vibrissae-related pattern of thalamocortical afferents (TCAs) in the posteromedial barrel subfield (PMBSF) of primary somatosensory cortex. We employed 5-HT immunocytochemistry or anterograde transport of 1′1′-dioctadecyl-3,3,3′,3′ tetramethyl-indocarbocyanin (Di-I) to label TCA arbors to study the effects of 5-HT manipulations on space occupied by TCAs within the PMBSF and the total area labeled. In rats treated to increase cortical 5-HT from birth to postnatal day (P) 6, the percentage of PMBSF area occupied by terminal labeling was significantly higher from that in controls (79.0% versus 23.7%, P < 0.05) for the highest levels of cortical 5-HT and was raised, although not significantly, for lower levels of 5-HT. The TCA coverage was significantly correlated with treatment dose. In animals exposed to a selective 5-HT1B agonist, 5-nonyloxytryptamine, or elevated endogenous 5-HT, the total areas of TCA aggregates in the PMBSF and those in visual cortex were similar to the controls. These results suggest that TCAs have a graded response to increasingly higher 5-HT concentrations. The lack of TCA expansion beyond normal cortical areas further implies that 5-HT-induced axon outgrowth is restricted at cortical boundaries.

PURPOSE: Aerobic running capacity (ARC) is a complex quantitative trait, determined by multiple genetic and environmental factors. Many physiological changes occur during exercise, including levels of endogenous opioids, specifically b-endorphins that can act as neurohormones and neurotransmitters throughout the peripheral and central nervous systems. Endorphins have many effects, including "exercise-induced euphoria," positive mood changes, modified pain perception andmetabolism. METHODS: The impact of beta-endorphins in determining ARC was studied in a rat genetic model. Beta-endorphin levels in plasma and brain regions were studied with ELISA assays using antibodies specific for beta-endorphin in 11 week-old male rats from three inbred strains [DA, a high performing strain and Copenhagen (COP) and Buffalo (BUF), low performing strains]. Experimental rat groups were studied following a single treadmill run to exhaustion and compared with control rats, which were not run. Two-way ANOVA was used to identify significant differences in beta-endorphin levels, with P < 0.05 the criterion for significance. RESULTS: Basal plasma beta-endorphin levels were significantly different among the three strains [COP (n=19, 1.46±0.22 ng/ml), BUF (n=12, 5.52±0.54 ng/ml), and DA (n=14, 2.68±0.56 rats; P < 0.00001). A Games-Howell post hoc test found significant differences between DA and BUF and between BUF and COP rats. Significantly increased plasma beta-endorphin levels were also observed between rats after the single treadmill run compared to control rats (n=18, 3.56±0.62 ng/ml and n=27, 2.50±0.39 ng/ml, respectively; P=0.0008), but there was no significant interaction between these two factors. A significant difference in beta-endorphin levels in the periaquaductal area of the brain was observed among the three strains (P=0.032). A PLSD post hoc test indicated a significant difference in periaquaductal beta-endorphin between COP (1.69±0.36 ng/ml) and BUF (2.87±0.31 ng/ml) rats (P=0.014). No significant differences in beta-endorphin levels were observed in the remaining brain regions examined: (striatum, thalamus, and hypothalamus) studied in these rats. SIGNIFICANCE: This study indicates that the observed strain-differences in beta-endorphin levels may contribute, in part, to the strain-differences in ARC seen in this model and that these inbred rat strains constitute a suitable genetic substrate for studying the basis for heritable strain differences in beta-endorphin levels.

In adult rats that sustained forelimb amputation on the day of birth, >30% of multiunit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) also respond to cutaneous hindlimb stimulation when cortical GABA(A+B) receptors are blocked (GRB). This study examined whether hindlimb receptive fields could also be revealed in forelimb-stump sites by reducing one known source of excitatory input to SI GABAergic neurons, the contralateral SI cortex. Corpus callosum projection neurons connect homotopic SI regions, making excitatory contacts onto pyramidal cells and interneurons. Thus in addition to providing monosynaptic excitation in SI, callosal fibers can produce disynaptic inhibition through excitatory synapses with inhibitory interneurons. Based on the latter of these connections, we hypothesized that inactivating the contralateral (intact) SI forelimb region would "unmask" normally suppressed hindlimb responses by reducing the activity of SI GABAergic neurons. The SI forelimb-stump representation was first mapped under normal conditions and then during GRB to identify stump/hindlimb responsive sites. After GRB had dissipated, the contralateral (intact) SI forelimb region was mapped and reversibly inactivated with injections of 4% lidocaine, and selected forelimb-stump sites were retested. Contralateral SI inactivation revealed hindlimb responses in approximately 60% of sites that were stump/hindlimb responsive during GRB. These findings indicate that activity in the contralateral SI contributes to the suppression of reorganized hindlimb receptive fields in neonatally amputated rats.

Studies of sensory pathways in several species indicate that the extent and form of reorganization resulting from deafferentation early in life vs. adulthood are not the same. The reasons for such differences are not well understood. To gain further insight into age‐dependent mechanisms of reorganization, this study compared the consequences of neonatal vs. adult forelimb amputation in rats at multiple levels of the sensory pathway, including primary somatosensory cortex, brainstem, and dorsal root ganglia. At the cortical level, the average area of the functional forelimb‐stump representation from rats amputated as adults was significantly smaller (P < 0.05) than that of neonatally amputated rats (4.3 ± 1.3 mm2 vs. 6.6 ± 1.5 mm2, respectively). At the brainstem level, neonatally amputated rat cuneate neurons possessed the following responsivities: 20% stump responsive, 40% responsive to both stump and hindlimb, 30% responsive to another body region, and 10% unresponsive. In contrast, cuneate neurons of adult amputated rats were 70% stump responsive, 2% responsive to both stump and hindlimb, and 30% unresponsive. A significantly (P < 0.001) greater percentage of the C6‐C8 dorsal root ganglia neurons of adult amputated rats were unresponsive to peripheral stimulation vs. neurons from neonatally amputated rats (48% vs. 16%, respectively). These results indicate that the reorganization that occurs in response to forelimb amputation at birth vs. adulthood is distinctly different at each of these levels of the dorsal column–medial lemniscal pathway. Possible mechanisms to account for these differences are considered. J. Comp. Neurol. 465:335–348, 2003. © 2003 Wiley‐Liss, Inc.

Rats that sustain forelimb removal on postnatal day (P) 0 exhibit numerous multi-unit recording sites in the forelimb-stump representation of primary somatosensory cortex (SI) that also respond to hindlimb stimulation when cortical GABAA+B receptors are blocked. Most of these hindlimb inputs originate in the medial SI hindlimb representation. Although many forelimb-stump sites in these animals respond to hindlimb stimulation, very few respond to stimulation of the face (vibrissae or lower jaw), which is represented in SI just lateral to the forelimb. The lateral to medial development of SI may influence the capacity of hindlimb (but not face) inputs to "invade" the forelimb-stump region in neonatal amputees. The SI forelimb-stump was mapped in adult (>60 days) rats that had sustained amputation on embryonic day (E) 16, on P0, or during adulthood. GABA receptors were blocked and subsequent mapping revealed increases in nonstump inputs in E16 and P0 amputees: fetal amputees exhibited forelimb-stump sites responsive to face (34%), hindlimb (10%), and both (22%); neonatal amputees exhibited 10% face, 39% hindlimb, and 5% both; adult amputees exhibited 10% face, 5% hindlimb, and 0% both, with approximately 80% stump-only sites. These results indicate age-dependent differences in receptive-field reorganization of the forelimb-stump representation, which may reflect the spatiotemporal development of SI. Results from cobalt chloride inactivation of the SI vibrissae region and electrolesioning of the dysgranular cortex suggest that normally suppressed vibrissae inputs to the SI forelimb-stump area originate in the SI vibrissae region and synapse in the dysgranular cortex.

Previous studies have shown that intracortical projections in layer IV of the vibrissae representation of primary somatosensory cortex (S-I) are arrayed in a pattern complementary to that of thalamocortical axons (TCAs). Elevation of cortical serotonin (5-HT) in rats during the first postnatal week results in a transient disruption of the vibrissae-related pattern of TCAs and layer IV neurons in S-I. The present study examines the influence of elevated cortical 5-HT levels and the attendant loss of vibrissae-related TCA clusters on the organization of S-I intracortical connections. Cortical 5-HT was elevated in neonatal rats via chronic injections of clorgyline from birth until P-6. Animals were euthanized on P-6 or allowed to survive an additional 4 days without further clorgyline treatment. Distributions of TCAs and intracortical axons were assessed via application of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Di-I) and 4-(4-(dihexadecylamino)styryl)-N-methylpyridinium iodide (Di-A) to the thalamic radiations and directly into the cortical barrelfield, respectively. Chronic administration of clorgyline resulted in a loss of the vibrissae-related organization of TCAs in layer IV of S-I. There was also a loss of the complementary pattern of intracortical projections in layer IV of this region. Discontinuation of clorgyline treatment resulted in a return of the vibrissae-related pattern of TCAs as well as the complementary pattern of intracortical projections. These results are consistent with the conclusion that the normal organization of intracortical projections in this region of S-I depends on the presence of the orderly array of TCAs.

Elevating cortical serotonin (5-HT) in rats from postnatal day (P-) 0 to P-6 by administering the monoamine oxidase (MAO(A)) inhibitor, clorgyline, produces a dose-dependent spectrum of effects on rat somatosensory organization, ranging from enlarged with indistinct septa to a complete lack of vibrissae-related patterns. However, if clorgyline treatment is stopped on P-6, a qualitatively and quantitatively normal vibrissae-related pattern of thalamocortical afferents appears in somatosensory cortex (S-I) on P-10. We employed high performance liquid chromatography (HPLC), infraorbital nerve (ION) transection, N-methyl-D-aspartate (NMDA) receptor blockade, 1,1'-dioctadecyl-3,3,3"3'-tetramethylindocarbocyanine perchlorate (DiI) labeling of thalamic afferents, and CO histochemistry to determine whether peripheral nerve input and/or cortical NMDA receptor activity were required for the recovery of vibrissae-related patterns in clorgyline-treated animals. Clorgyline administration from P-0 to P-6 produced a 1589.4+/-53.3% increase in cortical 5-HT over control animals on P-6 and a 268.8+/-6.3% elevation over controls at P-10. Postnatal day 6 pups had significantly altered vibrissae-related patterns in S-I following 6 days of clorgyline treatment but by P-10, the characteristic vibrissae-related patterns were restored. Neither transection of the ION nor application of the NMDA antagonist, DL-2-amino-5-phosphonovaleric acid (APV), to the cortices of P-6 pups that were treated with clorgyline from birth had any significant effect on the recovery of the vibrissae-related patterns by P-10. These results indicate that neither peripheral nerve input nor cortical NMDA receptor activity are necessary for the restoration of cortical vibrissae-related patterns in rats that have sustained transient elevations of 5-HT.

Neonatal transection of, or blockade of axoplasmic transport in, the infraorbital nerve [ION, the trigeminal (V) branch that supplies the mystacial vibrissae follicles] results in a loss of all central patterns corresponding to the vibrissae follicles in the brainstem, thalamus and cortex except for those of the central terminal arbors of ION primary afferents that survive this lesion. Both of these manipulations also result in a rapid and dramatic upregulation of at least two peptides, galanin and neuropeptide Y, in surviving vibrissae-related primary afferents. Galanin is of particular interest, because this peptide has effects on neuronal activity and growth, both factors which may be involved in the disappearance of central vibrissae-related patterns in rats that have sustained neonatal ION transection or axoplasmic transport blockade. The present study used antisense technology to determine whether the upregulation of galanin in the central terminals of ION primary afferents is necessary for the loss of central vibrissae-related patterns in rats. Newborn rats had their left ION transected or axoplasmic transport in this nerve blocked by application of a vinblastine-impregnated implant, and at the same time received an injection of commercially synthesized phosphorothioate oligodeoxynucleotide sequences (15-20 bases) directly into the V ganglion in order to block galanin upregulation. These injections effectively prevented the upregulation of this peptide which is normally associated with ION transection or axoplasmic transport blockade. Preventing galanin upregulation, however, did not prevent or attenuate the loss of central vibrissae-related patterns in the brainstem or cortex normally observed following ION transection or axoplasmic transport blockade in this nerve. These results are thus consistent with the conclusion that the upregulation of galanin in the central terminals of V primary afferents, observed after damage to or attenuation of axoplasmic transport in the ION, is not necessary for the reorganization that results in a disappearance of central vibrissae-related patterns in the V neuraxis.

We have previously shown that attenuation of axoplasmic transport by application of vinblastine to the developing infraorbital nerve (ION) results in a loss of central vibrissae-related patterns that is not accompanied by changes in the receptive field sizes for the V primary afferents innervating the whisker follicles. The present study examines the relationship between the loss of central vibrissae-related patterns and alterations in the response properties of neurons in the V principal sensory nucleus (PrV) of adult rats that sustained application of vinblastine to the ION at birth. Absence of histochemically demonstrable vibrissae-related patterns in PrV resulted in only modest changes in the receptive fields and response properties of vibrissae-sensitive neurons in this nucleus that projected to the contralateral thalamus. Response latencies to electrical activation of the V ganglion were similar in treated and untreated animals. The mean receptive field size was significantly increased from 1.3 +/- 0.7 vibrissae in controls to 1.7 +/- 0.9 vibrissae in vinblastine-treated animals, and the percentage of cells yielding a tonic response to vibrissae deflection was markedly reduced (p < 0.01 for both measures). Phasically responding cells recorded in vinblastine-treated animals showed a significant reduction in the mean number of spikes per stimulus following deflection of the vibrissae in either the preferred or non-preferred direction relative to cells recorded in normal animals (p < 0.05). The present results indicate that disruption of the normal vibrissae-related aggregates of neurons in PrV by application of vinblastine to the ION has limited effects on the functional representation of the vibrissae in this nucleus.