The neurogenic phase of angiotensin II-salt hypertension is prevented by chronic intracerebroventricular administration of benzamil.

Physiol Rep. 2014 Feb 26;2(2):e00245. Osborn JW, Olson DM, Guzman P, Toney GM, Fink GD. “Hypertension induced by chronic administration of angiotensin II (AngII) is exacerbated by high‐salt intake”. The authors from this study tested whether intracerebroventricular (ICV) administration of the sodium channel/transporter blocker benzamil would prevent AngII‐induced hypertension. As previously known, high salt diet with AngII increased mean arterial pressure in the presence of ICV vehile administration. Benzamil administration ICV had effect on MAP changes only after day 5 and reversed Ang II-induced MAP to control levels by day 13. Sodium or water balance was not different between the control and treatment groups. The results from this study suggest that sodium channels and/or transporters in the brain play a role in mediating AngII salt hypertension. However the molecular targets or the precise locations (within the brain) at which benzamil acts are unknown. It would be interesting to pursue this in the future studies.- Madhan

Altered sympathetic reflexes and vascular reactivity in rats after exposure to chronic intermittent hypoxia.

J Physiol. 2011 Mar 15;589(Pt 6):1463-76. Silva AQ, Schreihofer AM. “Exposure to chronic intermittent hypoxia (CIH) yields persistent elevations in sympathetic nerve activity (SNA) and mean arterial pressure (MAP) with exaggerated sympathetic chemoreflexes”. The authors determined whether rats that were exposed to CIH produce exaggerated sympathetic responses. They hypothesized that sympathetic reflexes initiated by peripheral nerves would be exaggerated after exposure to CIH. They also determined whether exposure to CIH enhanced sympathoexcitation produced by glutamatergic stimulation of the RVLM. The authors found that sympathoexcitatory reflexes initiated by peripheral nerves other than the carotid sinus nerve produced exaggerated increase in SNA after exposure to CIH. Also stimulation of the RVLM, produced an augmented increase in SNA after CIH. Interestingly, the sympathoexcitatory responses were not accompanied by enhanced pressor changes. This could be because of reduced pressor reactivity to adrenergic stimulation seen after CIH. To summarize, the authors suggest that sympathoexciatory responses may be exaggerated because of increased excitability of the RVLM and reduced adrenergic vascular reactivity after exposure to CIH.-Madhan

Modulation of the sympathetic response to acute hypoxia by the caudal ventrolateral medulla in rats.

J Physiol. 2009 Jan 15;587(Pt 2):461-75. Mandel DA, Schreihofer AM. “Hypoxia elevates splanchnic sympathetic nerve activity (SNA) with differential effects during inspiration and expiration by unresolved central mechanisms”. The authors tested the hypothesis whether baro-activated CVLM neurons contribute to sympathetic responses to acute hypoxia. Additionally the authors also tested whether selective inhibition of excitatory or inhibitory actions on the CVLM would alter the sympathetic responses to hypoxia. In this study, the authors demonstrated that stimulation of peripheral chemoreceptors by hypoxia produced differential responses in baro-activated CVLM neurons. Blocking excitation and inhibition of the CVLM augmented or reduced the sympathetic response to acute hypoxia respectively. This suggests that both glutamate and GABA in the CVLM could be involved in mediated sympathetic responses to acute hypoxia.-Madhan

Angiotensin II slow-pressor hypertension enhances NMDA currents and NOX2-dependent superoxide production in hypothalamic paraventricular neurons.

Am J Physiol Regul Integr Comp Physiol. 2013 Jun 15;304(12):R1096-106. Wang G1, Coleman CG, Chan J, Faraco G, Marques-Lopes J, Milner TA, Guruju MR, Anrather J, Davisson RL, Iadecola C, Pickel VM. “Adaptive changes in glutamatergic signaling within the hypothalamic paraventricular nucleus (PVN) may play a role in the neurohumoral dysfunction underlying the hypertension induced by "slow-pressor" ANG II infusion”. To test their hypothesis, the authors performed several elegant experiments. In experiment 1, the authors used electron microscope immunolabelling to show that in the PVN dendrities of ang II infused mice, there was colocalization of NOX2 and N-methyl-D-aspartate receptor (NMDAR) NR1 subunits. In experiment 2, there was increased reactive oxygen species but decreased nitric oxide (NO) production at baseline and after NMDA administration in cells isolated from ang II infused mice. In experiment 3, NMDA induced increases in inward current shown by whole cell recording in spinally projecting PVN cells in slices was reversed by ROS scavenger and NO donor in ang II group. These experiments clearly demonstrated the relationship between enhanced glutamatergic signaling in the PVN and other well-known mechanisms that are involved in the development of ang II slow-pressor hypertension.-Madhan

Membrane trafficking of NADPH oxidase p47(phox) in paraventricular hypothalamic neurons parallels local free radical production in angiotensin II slow-pressor hypertension.

J Neurosci. 2013 Mar 6;33(10):4308-16. Coleman CG1, Wang G, Faraco G, Marques Lopes J, Waters EM, Milner TA, Iadecola C, Pickel VM. “NADPH oxidase-generated reactive oxygen species (ROS) are highly implicated in the development of angiotensin II (AngII)-dependent hypertension mediated in part through the hypothalamic paraventricular nucleus (PVN)”. The authors tested the role of vasopressin and non-vasopressin neurons in the production of ROS in the PVN of ang II slow-pressor hypertension model. In the first set of experiments, the authors used ROS imaging to first confirm the increased production of ROS in ang II slow-pressor mice. Then the authors examined the baseline and NMDA induced ROS levels in vasopressin and non-vasopressin cells. Interestingly they found increased ROS production in vasopressin cells after NMDA infusion in ang II groups, however in non vasopressin cells the levels were increased in both the ang II groups and control groups. In the second set of examined the authors used electron microscopic dual labeling for vasopressin and a NADPH oxidase subunit, that was important for the production of ROS. The immunolabeling for p47 phox was decreased in the plasma membrane and increased in membranes just beneath the plasmalemmal surface in vasopressin and non-vasopressin cells of ang II mice respectively. Based on these findings the authors arrive at an interesting conclusion suggesting that the membrane assembly of vasopressin and non-vasopressin cells were differentially affected in the PVN of ang II slow-pressor model offsetting the homeostatic control of blood pressure.-Madhan

Exercise training attenuates hypertension and cardiac hypertrophy by modulating neurotransmitters and cytokines in hypothalamic paraventricular nucleus.

PLoS One. 2014 Jan 17;9(1):e85481. Jia LL, Kang YM, Wang FX, Li HB, Zhang Y, Yu XJ, Qi J, Suo YP, Tian ZJ, Zhu Z, Zhu GQ, Qin DN. “Regular exercise as an effective non-pharmacological antihypertensive therapy is beneficial for prevention and control of hypertension, but the central mechanisms are unclear”. The authors investigated whether exercise training in spontaneously hypertensive rats (SHRs) could delay the progression of hypertension and reduce cardiac hypertrophy in them by balancing the excitatory and inhibitory neurotransmitters and pro and anti-inflammatory cytokines in the paraventricular nucleus (PVN). The rats were treadmill trained from 7 to 16 weeks. The authors observed that sedentary SHRs had higher mean arterial pressure and cardiac hypertrophy and these factors were significantly attenuated in the exercise trained SHRs. They authors found that sedentary SHRs had greater concentration of glutamate and norepinephrine and lower concentration of GABA in the PVN compared to their exercise trained counterparts. The authors also measured a number of pro and anti-inflammatory cytokines in the PVN and plasma to suggest that these factors could be involved in mediating reduced sympathetic nerve activity and blood pressure observed in the exercise trained SHRs compared to sedentary SHRs. More translational approach would take these findings along with other similar findings to the next level.-Madhan

Exercise training lowers the enhanced tonically active glutamatergic input to the rostral ventrolateral medulla inhypertensive rats.

CNS Neurosci Ther. 2013 Apr;19(4):244-51. Zha YP, Wang YK, Deng Y, Zhang RW, Tan X, Yuan WJ, Deng XM, Wang WZ. “It is well known that low-intensity exercise training (ExT) is beneficial to cardiovascular dysfunction in hypertension”. The authors investigated the effects of exercise training on glutamatergic inputs in the RVLM of a spontaneously hypertensive rats. The animals were treadmill trained for about 12 weeks. The authors observed that exercise trained SHR rats had significantly blunted responses of arterial pressure, heart rate and renal sympathetic nerve activity to bilateral microinjection of Kynurenic acid in the RVLM compared to sedentary SHRs. The authors found that exercise trained SHRs had reduced glutamate concentration (measured by HPLC) and the lower protein expression of vesicular glutamate transporter 2 (that packs the glutamate in the presynaptic terminal). The authors suggest that exercise training lowered the enhanced glutamatergic input in the RVLM in SHRs and this could be the possible mechanism by which it reduced blood pressure and sympathetic nerve activity in them.-Madhan

Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo.

Neuroscience. 2004;124(1):71-9. Farmer J, Zhao X, van Praag H, Wodtke K, Gage FH, Christie BR. “Voluntary exercise produces enhanced neurogenesis and long-term potentiation (LTP) in the dentate gyrus (DG) of mice in vitro”. In the present study, the authors investigated the mechanisms by which voluntary activity increased neurogenesis. First they confirmed that voluntary exercise increased neurogenesis and LTP in the DG of rats in vivo. Second they showed LTP could be easily achieved in rats performing voluntary exercise and finally they suggested that the functional changes might be mediated through increased expression of BDNF, NR2B and GLUR5 mRNA at cellular level in voluntary running animals.-Madhan

Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.

Nat Neurosci. 1999 Mar;2(3):266-70. van Praag H, Kempermann G, Gage FH. “Exposure to an enriched environment increases neurogenesis in the dentate gyrus of adult rodents”. In this study the authors exposed the animals to various factors such as enriched environment, hidden-platform water maze learning, forced exercise, voluntary exercise and control housing conditions and tested their effects on adult hippocampal cell proliferation and neurogenesis. The authors injected BrdU intraperitoneally to study the proliferation of living hippocampal neurons. They found that mice that were allowed to run voluntarily had increased cell proliferation and number of newborn cells in the dendate gyrus was approximately doubled under voluntary activity and enrichment. On the other hand, mice that were trained in water maze or swim control does not show neurogenesis in adult hippocampal neurons. This study suggests that voluntary running enhances cell proliferation, survival and differentiation in adult hippocampal neurons.-Madhan

Glutamatergic receptor activation in the rostral ventrolateral medulla mediates the sympathoexcitatory response to hyperinsulinemia.

Hypertension. 2010 Feb;55(2):284-90. Bardgett ME, McCarthy JJ, Stocker SD. “Hyperinsulinemia increases sympathetic nerve activity (SNA) and has been linked to cardiovascular morbidity in obesity. The rostral ventrolateral medulla (RVLM) plays a key role in the regulation of SNA and arterial blood pressure (ABP)”. The authors tested the hypothesis whether glutamatergic receptor activation in the RVLM mediate sympathoexcitatory response to hyperinsulinemia. Microinjection of kynurenic acid, a glutamate receptor antagonist, into the RVLM significantly reduced lumbar sympathetic nerve activity during hyperinsulinemic euglycemic clamps in rats. On the other hand, insulin microinjection directly into the RVLM did not alter lumbar sympathetic nerve activity. Taken together these findings provided insight into the potential neural pathways and signaling mechanisms involved in insulin mediated increases in central sympathetic outflow and suggest that an excitatory glutamatergic pathway to the brainstem may be involved in insulin stimulated sympatho-excitation.- Madhan

Excess dietary salt alters angiotensinergic regulation of neurons in the rostral ventrolateral medulla.

Hypertension. 2008 Nov;52(5):932-7. Adams JM, McCarthy JJ, Stocker SD. “Excess dietary salt intake contributes to or exacerbates some forms of hypertension by increasing sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through angiotensin II (Ang II) type 1 receptor activation in the rostral ventrolateral medulla (RVLM)”. The authors tested the hypothesis whether dietary salt alone alters angiotensinergic regulation of neurosn in the RVLM. Microinjection of Ang II into the RVLM significantly increased renal sympathetic nerve activity and mean arterial blood pressure in rats that we allowed to drink water with 0.9% NaCl for 14 days. Blockade of Ang II type 1 receptors in the RVLM significantly reduced renal, splanchnic SNA and mean arterial blood pressure suggesting that neurons in the RVLM that regulate angiotensinergic mechanisms are altered by excess dietary salt.- Madhan

Exercise-induced activation of NMDA receptor promotes motor unit development and survival in a type 2 spinal muscular atrophy model mouse.

J Neurosci. 2008 Jan 23;28(4):953-62. Biondi O, Grondard C, Lécolle S, Deforges S, Pariset C, Lopes P, Cifuentes-Diaz C, Li H, della Gaspera B, Chanoine C, Charbonnier F. “Spinal muscular atrophy (SMA) is an inborn neuromuscular disorder caused by low levels of survival motor neuron protein, and for which no efficient therapy exists”. The authors have previously shown that running enhanced motor neuron function and increased life span in type 2 SMA-like mice. In the present study, the authors investigated whether there is a direct relationship between maturation state of a motor neurons and resistance to neuronal cell death. Further they report the signaling pathway by which exercise provides neuroprotection in SMA-like mice. They report their findings after performing a series of experiments in a knock-out transgenic SMA-like mice. The authors report that exercise leads to a delay in motor-neuron death, which is independent of the rate of postnatal motor-unit maturation. In the spinal cord motor neurons of neonatal SMA-like mice the authors observed a defective expression of NR2A subunit. In addition, the expression of NR2A subunit is enhanced in the trained SMA-like mice suggesting that this could contribute to NMDA-receptor activation in type 2 SMA-like mice. Further, the authors inhibited NMDA-receptor activity to show that exercise-induced benefits in the trained type 2 SMA-like mice were suppressed. The authors conclude that restoring the function of NMDA receptor could be a potential treatment for SMA.- Madhan

In vivo NMDA receptor activation accelerates motor unit maturation, protects spinal motor neurons, and enhances SMN2 gene expression in severe spinal muscular atrophy mice.

J Neurosci. 2010 Aug 25;30(34):11288-99. Biondi O, Branchu J, Sanchez G, Lancelin C, Deforges S, Lopes P, Pariset C, Lécolle S, Côté J, Chanoine C, Charbonnier F. “Spinal muscular atrophy (SMA), a lethal neurodegenerative disease that occurs in childhood, is caused by the misexpression of the survival of motor neuron (SMN) protein in motor neurons”. In the present study, the authors evaluated whether activation of NMDA receptor in a type 2 SMA mouse affects SMN expression and motor neuron survival in SMA spinal cord. The authors reported the level at which NMDA receptor gets activated could provide beneficial or detrimental effects. At adequate level it could accelerate motor unit maturation, prevention of the spinal motor neurons from apoptosis and modification of SMN2 expression. At higher levels of activation, it could provide opposite effects. Further activation of NMDA receptor lead to reactivation of downstream signaling pathway enhancing SMN expression suggesting that activation of NMDA receptor at adequate levels could be used in enhancing SMN expression and reducing motor neuron death in SMA spinal cord. - Madhan

Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray.

Eur J Neurosci. 2002 Sep;16(6):1107-16. Molteni R, Ying Z, Gómez-Pinilla F. In this study the authors determined the effects of acute and chronic voluntary periods of exercise on the expression of genes in the hippocampus. The authors used a predesigned microarray with 1176 cDNAs primarily expressed in the brain. The animals were allowed to run voluntarily for a period of 3, 7 and 28 days. Sedentary animals were used as control. Genes associated with glutamatergic system such as NMDAR-2A, NMDAR-2B and excitatory amino acid carrier-1 was upregulated, where as GABAA receptor and GAD 65 were down-regulated. BDNF genes were consistently up-regulated across all different exercise groups. The authors hypothesized a potential mechanism by which exercise modulates neuronal plasticity in the hippocampus. It was suggested elevated BDNF expression under active conditions could affect both the pre and post synaptic terminals. TrKB receptor, the primary mediator of BDNF was also up-regulated in active animals. TrKB signaling affected the up-regulation of several downstream genes such as MAP-KI, MAP-KII, PKC gamma and CaM-KII. The authors also suggest that exercise could affect the pre synaptic genes such as synapsin, synaptotagmin and syntaxin to modulate the release of neurotransmitters such as glutamate. In the post synaptic terminal, the effects of exercise could be mediated by calcium influx through the NMDA receptor. The expression of calcium2+/calmodulin dependent protein kinase II was also up-regulated in exercise, which could activate the MAP-K cascade. Activated MAP-K could act on a nuclear target, transcription factor CREB, the expression of which is also up-regulated in exercise. -Madhan

Physical Exercise Prevents Stress-Induced Activation of Granule Neurons and Enhances Local Inhibitory Mechanisms in the Dentate Gyrus

J Neurosci. 2013 May 1;33(18):7770-7. Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, Gould E. “Physical exercise is known to reduce anxiety”. The ventral hippocampus is an important region that is involved in the regulation of stress and anxiety. In this study, the authors investigated the effects of exercise (running) on the ventral hippocampus after subjecting the animals to anxiety provoking stimulus. The authors tested the expression of c-fos and arc as an indirect measure to evaluate neuronal activation after performing cold water swim stress in sedentary and running mice. Stress increased the expression of the proteins tested under sedentary condition but not under active condition. In order to test whether running modifies the inhibitory activation to a stressor, the authors measured the expression of c-fos and arc by inhibitory interneurons, amount of GABA release and expression of vesicular GABA transporter (vGAT) in the hippocampus. Running increased the local inhibitory mechanisms in the hippocampus, showed by enhanced expression of vGAT and extracellular GABA release during cold water swim stress. Further blocking of GABAA receptors with bicuculline in the ventral hippocampus reversed the anxiolytic effect of running. These findings suggest that the running plays an important role in improving the regulation of anxiety through inhibitory mechanisms in the ventral hippocampus. - Madhan

Median preoptic nucleus and subfornical organ drive renal sympathetic nerve activity via a glutamatergicmechanism within the paraventricular nucleus.

Am J Physiol Regul Integr Comp Physiol. 2012 Feb 15;302(4):R424-32. Llewellyn T, Zheng H, Liu X, Xu B, Patel KP. “The paraventricular nucleus (PVN) of the hypothalamus is involved in the neural control of sympathetic drive, but the precise mechanism(s) that influences the PVN is not known”. The authors hypothesized that glutamatergic activation of higher brain centers such as the median preoptic nucleus (MnPO) and subfornical organ (SFO) could influence PVN. To test this hypothesis, the authors performed several microinjection experiments. First they injected a retrograde tracer into the PVN and visualized it in the MnPO and SFO confirming a neuroanatomical connection. Second they activated MnPO by microinjection of NMDA or bicuculline and demonstrated an increase in RSNA, blood pressure and heart rate. To test whether these effects are mediated through PVN, they blocked PVN using AP5 (glutamate receptor blocker) and repeated the experiment and found MnPO activation after blocking PVN does not produce the same cardiovascular effects, suggesting the effects are mediated through PVN. Further firing activity of PVN neurons were tested by activation of neurons in the MnPO. Finally, similar to MnPO, SFO was activated before and after blockade of PVN. Changes in RSNA, blood pressure and heart rate were recorded. The findings from this study suggest that glutamatergic activation of the PVN is at least partially mediated by activation of MnPO and SFO. -Madhan

Effects of exercise training on SFO-mediated sympathoexcitation during chronic heart failure.

Am J Physiol Heart Circ Physiol. 2014 Jan;306(1):H121-31. Llewellyn TL, Sharma NM, Zheng H, Patel KP. “Exercise training (ExT) has been shown to reduce sympathetic drive during heart failure (HF)”. Recently the authors from this laboratory showed that the paraventricular nucleus (PVN) of the hypothalamus was activated in rats with HF and exercise training (EXT) normalized this effect but the mechanisms that mediate the enhanced activation of the PVN are unknown. Subfornical organ (SFO) is a circumventricular organ that lacks blood brain barrier and has been shown to have neuronal connections with the PVN. In the present study, the authors hypothesized that SFO is activated in HF and contributes to the regulation of sympathetic drive in HF. To test this hypothesis, the authors performed several experiments. First, they induced HF in normal SD rats and found these rats had increased neuronal activity in the SFO compared to normal rats. Second, angiotensin II was microinjected in the SFO, which increased renal SNA, blood pressure and heart rate in the HF animals compared to rats without HF. Third, Losartan (AT1 receptor blocker) was microinjected in the SFO to confirm that angiotensin II effects are mediated through AT1 receptor. Losartan decreased RSNA in HF rats. Finally biochemical changes of AT1 receptors in the SFO showed elevated expression in HF rats. Exercise treatment reversed the changes at each experimental condition. These findings suggests that enhanced ang II in the SFO contributes to the activation of SFO and in turn leads to sympathoexcitation in HF and these effects could be reversed by exercise training. - Madhan

Inhibition of brown adipose tissue thermogenesis by neurons in the ventrolateral medulla and in the nucleus tractus solitarius.

Am J Physiol Regul Integr Comp Physiol. 2010 Jul;299(1):R277-90. Cao WH, Madden CJ, Morrison SF “Neurons in the ventrolateral medulla (VLM) and in the nucleus tractus solitarius (NTS) play important roles in the regulation of cardiovascular and other autonomic functions”. In this study, the authors demonstrated how activation of neurons in the VLM and intermediate NTS affected brown adipose tissue (BAT) thermogenesis. The authors performed a series of microinjection experiment in chloralose/urethane-anesthetized rats to test their hypothesis. First they tested the effects of activation of neurons in the VLM on cold evoked BAT thermogenesis. NMDA (glutamate agonist) was injected in the VLM to observe that it reversed the cold-evoked increase in BAT SNA, thermogenesis and end-expired CO2. Second they tested the effects of disinhibition of neurons in the VLM or in the NTS on BAT thermogenesis under different conditions using bicuculline (GABA-A receptor antagonist), which reversed the increase in BAT SNA, thermogenesis and end-expired CO2. Finally the tested the effects of inhibition of neurons in the VLM and NTS using muscimol (GABA-A receptor agonist), which produced increases in BAT SNA, thermogenesis and end-expired CO2. These effects were reversed using injection of glycine in the rRPa. These findings suggest that BAT thermogenesis is inhibited by activation of VLM and NTS neurons. -Madhan

α2 Adrenergic receptor-mediated inhibition of thermogenesis.

J Neurosci. 2013 Jan 30;33(5):2017-28. Madden CJ, Tupone D, Cano G, Morrison SF. “α2 adrenergic receptor (α2-AR) agonists have been used as antihypertensive agents, in the management of drug withdrawal, and as sedative analgesics”. In this study, the authors investigated the effects of α2-AR agonists as antipyretic agents. Clonidine (α2-AR agonist) was administered into the rostral raphe pallidus area (neurons in this region regulate sympathetic outflow to brown adipose tissue (BAT), which regulates thermogenesis), which inhibited BAT sympathetic nerve activity and thermogenesis. The authors reversed the effects of clonidine injection by administration of α2-AR antagonist idazoxan into rRPa. The effects of α2-AR agonists were also tested using systemic injections of its agonists, which produced responses similar to central administration. An interesting observation in the present study involves the use of CtB as a retrograde tracer from rRPa and pseudorabies virus as a transynaptic tracer from BAT to demonstrate that VLM was the source of catecholaminergic input to the rRPa and these neurons are synaptically connected to BAT. Furthermore, the authors used optogenetic technique to stimulate the neurons in the VLM and thereby activate 2-ARs in the rRPa, which inhibited BAT SNA. Taken together these findings suggest that α2-AR agonist can be used to treat excessive body temperature during fever. -Madhan

Voluntary Exercise Induces a BDNF-Mediated Mechanism That Promotes Neuroplasticity

FERNANDO GO´MEZ-PINILLA,1,2 ZHE YING,1 ROLAND R. ROY,3 RAFFAELLA MOLTENI,1 AND V. REGGIE EDGERTON1,3 1Department of Physiological Science, 2Division of Neurosurgery, UCLA Brain Injury Research Center and 3Brain Research Institute, Los Angeles, California 90095 Received 4 March 2002; accepted in final form 15 July 2002 “BDNF is a powerful modifier of neuronal excitability and synaptic transmission”. The authors were interested to determine whether exercise induces an integrated response of BDNF and its receptors that may lead to synaptic modification at the level of neuromuscular system. To test this, they allowed 3 months old male SD rats to exercise for a period of 3 days and 7 days in running wheel with increasing load over the time period. The authors selected the lumbar region of the spinal cord and soleus muscle to examine the changes since the motor pools innervating the hindlimb muscles are located in the lumbar region of the spinal cord and running involves recruitment of soleus muscle. Further to examine whether muscle activation via locomotion is the main stimulus for the induction of neurotrophins the authors paralyzed the soleus muscle with botulinum toxin in separate groups of animals. Voluntary exercise increased the mRNA expression of synapsin I, which mediates the action of BDNF. Synapsin I mRNA levels were increased in proportion to growth associated protein (GAP-43) and signal transduction receptor (trkB). These suggest that exercise can impact synaptic growth and function. Paralysis of soleus muscle resulted in reduced BDNF and synpasin I mRNA levels suggesting that basal level of neuromuscular activity is necessary to maintain normal levels of BDNF. Overall BDNF was shown to play an important role in exercise mediated neuronal plasticity and function in the neuromuscular system. -Madhan