Progesterone Sharpens Temporal Response Profiles of Sensory Cortical Neurons in Animals Exposed to Traumatic Brain Injury.

Traumatic brain injury (TBI) initiates a cascade of pathophysiological changes that are both complex and difficult to treat. Progesterone (P4) is a neuroprotective treatment option that has shown excellent preclinical benefits in the treatment of TBI, but these benefits have not translated well in the clinic. We have previously shown that P4 exacerbates the already hypoactive upper cortical responses in the short-term post-TBI and does not reduce upper cortical hyperactivity in the long term, and we concluded that there is no tangible benefit to sensory cortex firing strength. Here we examined the effects of P4 treatment on temporal coding resolution in the rodent sensory cortex in both the short term (4 d) and long term (8 wk) following impact-acceleration-induced TBI. We show that in the short-term postinjury, TBI has no effect on sensory cortex temporal resolution and that P4 also sharpens the response profile in all cortical layers in the uninjured brain and all layers other than layer 2 (L2) in the injured brain. In the long term, TBI broadens the response profile in all cortical layers despite firing rate hyperactivity being localized to upper cortical layers and P4 sharpens the response profile in TBI animals in all layers other than L2 and has no long-term effect in the sham brain. These results indicate that P4 has long-term effects on sensory coding that may translate to beneficial perceptual outcomes. The effects seen here, combined with previous beneficial preclinical data, emphasize that P4 is still a potential treatment option in ameliorating TBI-induced disorders.

Masking reduces orientation selectivity in rat visual cortex.

In visual masking the perception of a target stimulus is impaired by a preceding (forward) or succeeding (backward) mask stimulus. The illusion is of interest because it allows uncoupling of the physical stimulus, its neuronal representation, and its perception. To understand the neuronal correlates of masking, we examined how masks affected the neuronal responses to oriented target stimuli in the primary visual cortex (V1) of anesthetized rats (n = 37). Target stimuli were circular gratings with 12 orientations; mask stimuli were plaids created as a binarized sum of all possible target orientations. Spatially, masks were presented either overlapping or surrounding the target. Temporally, targets and masks were presented for 33 ms, but the stimulus onset asynchrony (SOA) of their relative appearance was varied. For the first time, we examine how spatially overlapping and center-surround masking affect orientation discriminability (rather than visibility) in V1. Regardless of the spatial or temporal arrangement of stimuli, the greatest reductions in firing rate and orientation selectivity occurred for the shortest SOAs. Interestingly, analyses conducted separately for transient and sustained target response components showed that changes in orientation selectivity do not always coincide with changes in firing rate. Given the near-instantaneous reductions observed in orientation selectivity even when target and mask do not spatially overlap, we suggest that monotonic visual masking is explained by a combination of neural integration and lateral inhibition.

Progesterone Exacerbates Short-Term Effects of Traumatic Brain Injury on Supragranular Responses in Sensory Cortex and Over-Excites Infragranular Responses in the Long Term.

Progesterone (P4) has been suggested as a neuroprotective agent for traumatic brain injury (TBI) because it ameliorates many post-TBI sequelae. We examined the effects of P4 treatment on the short-term (4 days post-TBI) and long-term (8 weeks post-TBI) aftermath on neuronal processing in the rodent sensory cortex of impact acceleration-induced diffuse TBI. We have previously reported that in sensory cortex, diffuse TBI induces a short-term hypoexcitation that is greatest in the supragranular layers and decreases with depth, but a long-term hyperexcitation that is exclusive to the supragranular layers. Now, adult male TBI-treated rats administered P4 showed, in the short term, even greater suppression in neural responses in supragranular layers but a reversal of the TBI-induced suppression in granular and infragranular layers. In long-term TBI there were only inconsistent effects of P4 on the TBI-induced hyperexcitation in supragranular responses but infragranular responses, which were not affected by TBI alone, were elevated by P4 treatment. Intriguingly, the effects in the injured brain were almost identical to P4 effects in the normal brain, as seen in sham control animals treated with P4: in the short term, P4 effects in the normal brain were identical to those exercised in the injured brain and in the long term, P4 effects in the normal brain were rather similar to what was seen in the TBI brain. Overall, these results provide no support for any protective effects of P4 treatment on neuronal encoding in diffuse TBI, and this was reflected in sensorimotor and other behavior tasks also tested here. Additionally, the effects suggest that mechanisms used for P4 effects in the normal brain are also intact in the injured brain.

Pioglitazone treatment enhances the sympathetic nervous system response to oral carbohydrate load in obese individuals with metabolic syndrome.

CONTEXT: Insulin resistance is associated with blunted sympathetic nervous system (SNS) response to carbohydrate ingestion which may contribute to postprandial hypotension and impaired body weight homeostasis. OBJECTIVE: This study was conducted to examine the effects of pharmacological insulin sensitization on whole-body norepinephrine kinetics during a standard 75-g oral glucose tolerance test (OGTT) in obese, insulin resistant subjects with metabolic syndrome. METHODS: Un-medicated individuals (n=42, mean age 56±0.8 yrs, body mass index 34±0.6 kg/m(2)) were randomised to 12-weeks pioglitazone (PIO, 15 mg for 6 weeks, then 30 mg daily) or placebo using a double-blind, parallel group design. Whole-body norepinephrine kinetics (arterial norepinephrine concentration, calculated spillover and clearance rates), spontaneous cardiac baroreflex sensitivity, heart rate and blood pressure were measured at times 0, 30, 60, 90 and 120 minutes during OGTT. Insulin sensitivity was assessed by euglycemic hyperinsulinemic clamp (M) and Matsuda index. RESULTS: PIO increased clamp derived glucose utilisation by 35% (P<0.001) and there were concurrent reductions in inflammatory status and plasma triglycerides (P<0.05). Fasting norepinephrine kinetic parameters were unaltered. PIO treatment was associated with lower plasma insulin incursions, greater reduction in diastolic blood pressure and enhanced baroreflex sensitivity during OGTT (P all <0.05). The overall norepinephrine spillover response (AUC(0-120)) increased significantly in the PIO group (group × time interaction, P=0.04), with greatest increment at 30 minutes post-glucose (101±38 ng/min at baseline versus 241±48 ng/min post treatment, P=0.04) and correlated with percent improvement in M. CONCLUSIONS: PIO enhances the early postprandial SNS response to carbohydrate ingestion.

A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome.

CONTEXT: Insulin resistance and sympathetic nervous system overactivity are closely associated and contribute to cardiovascular risk. OBJECTIVE: The objective of the study was to test the hypotheses that pharmacological improvement in insulin sensitivity would (1) attenuate sympathetic neural drive and (2) enhance neuronal norepinephrine uptake. PARTICIPANTS AND METHODS: A randomized, double-blind trial was conducted in 42 obese, unmedicated individuals with metabolic syndrome (mean age 56 ± 1 y, body mass index 34 ± 0.6 kg/m(2)) who received 12 weeks of pioglitazone (PIO; 15 mg for 6 wk, then 30 mg daily) or matched placebo. Clinical measurements included whole-body norepinephrine kinetics [spillover rate, plasma clearance, and the steady state ratio of tritiated 3,4-dihydroxyphenylglycol to tritiated norepinephrine ([(3)H]-DHPG to [(3)H]-NE) as an index of neuronal uptake-1], muscle sympathetic nerve activity, spontaneous baroreflex sensitivity, euglycemic hyperinsulinemic clamp, oral glucose tolerance test, ambulatory blood pressure, and Doppler echocardiography. RESULTS: PIO treatment increased glucose uptake by 35% and was accompanied by significant reductions in diastolic blood pressure and improved left ventricular diastolic and endothelial function. Resting muscle sympathetic nerve activity burst frequency decreased by -6 ± 3 burst/min compared with baseline (P = .03), but the magnitude of change was not different from placebo (P = .89). Norepinephrine spillover and clearance rates and baroreflex sensitivity were unchanged. Post hoc subgroup analyses revealed an 83% increase in [(3)H]-DHPG to [(3)H]-NE ratio in hyperinsulinemic (P = .04) but not normoinsulinemic subjects (time × group interaction, P = .045). Change in [(3)H]-DHPG to [(3)H]-NE ratio correlated with improvements in diastolic blood pressure (r = -0.67, P = .002), the ratio of early (E) to late (A) peak transmitral diastolic inflow velocity (r = 0.62, P = .008), E wave deceleration time (r = -0.48, P = .05), and Δinsulin area under the curve0-120 during the oral glucose tolerance test (r = -0.42, P = .08). CONCLUSIONS: Compared with placebo, PIO does not affect resting sympathetic drive or norepinephrine disposition in obese subjects with metabolic syndrome. Treatment induced changes in the [(3)H]-DHPG to [(3)H]-NE ratio related to reduction in hyperinsulinemia and improvements in diastolic function.

The effects of dietary weight loss on indices of norepinephrine turnover: modulatory influence of hyperinsulinemia.

OBJECTIVES: This study was conducted to examine (1) the effects of dietary weight loss on indices of norepinephrine (NE) turnover and (2) whether baseline hyperinsulinemia modulates sympathetic neural adaptations. METHODS: Obese individuals aged 56 ± 1 year, BMI 32.5 ± 0.4 kg/m(2) , with metabolic syndrome, underwent a 12-week hypocaloric diet (HCD, n = 39) or no treatment (n = 26). Neurochemical measurements comprised arterial dihydroxyphenylalanine (DOPA), 3,4-dihydroxyphenylglycol (DHPG), and NE concentrations, the steady-state ratio of [3H]-DHPG to [3H]-NE, as an index of neuronal uptake, and calculated whole-body plasma NE clearance and spillover rates. RESULTS: Body weight decreased by -7.4 ± 0.5% in HCD group (P < 0.001) and was accompanied by reductions in DOPA, NE, and DHPG averaging -14 ± 5% (P = 0.001), -23 ± 4% (P <0.001), and -5 ± 4% (P = 0.03), respectively. NE spillover rate decreased by -88 ± 39 ng/min (P = 0.01), whereas neuronal uptake and NE plasma clearance were unchanged. Despite similar weight loss, hyperinsulinemic subjects exhibited greater reductions in NE and NE spillover rate, compared to normoinsulinemic subjects (group by time interaction P < 0.05). CONCLUSIONS: Weight loss is associated with down-regulation of sympathetic nervous activity but no overall alteration in disposition indices. Hyperinsulinemic subjects derive a greater sympathoinhibitory benefit during weight loss.

The relation of glucose metabolism to left ventricular mass and function and sympathetic nervous system activity in obese subjects with metabolic syndrome.

CONTEXT: Altered cardiac structure and function have been reported in prediabetic and diabetic populations; however, the contribution of the sympathetic nervous system (SNS) to these changes has yet to be delineated. OBJECTIVE: Our objective was to examine interrelationships between glucose metabolism, left ventricular mass and function, and SNS activity in obese metabolic syndrome subjects. PARTICIPANTS AND METHODS: Unmedicated impaired glucose tolerant (IGT) (n = 31) or treatment-naive type 2 diabetic (T2D) (n = 25) subjects, matched for age (mean 58 ± 1 years), gender, body mass index (32.2 ± 0.5 kg/m(2)), and blood pressure, participated. They underwent echocardiography and assessments of whole-body norepinephrine kinetics, muscle sympathetic nerve activity, and insulin sensitivity by euglycemic clamp (M value). RESULTS: T2D subjects had higher left ventricular mass index (LVMI) (93.6 ± 3.5 vs 77.2 ± 3.4 g/m(2), P = .002) and Doppler-derived isovolumetric relaxation and deceleration times (both P < .05) and lower early/late transmitral inflow velocities (E/A) (P = .02) compared with IGT. Total muscle sympathetic nerve activity and arterial norepinephrine concentration were higher in the T2D group (by 18% and 32%, respectively, both P ≤ .05), whereas plasma norepinephrine clearance was reduced (1.94 ± 0.11 vs 2.26 ± 0.10 L/min, P = .02). M value correlated inversely with left ventricular septal thickness (r = -0.46, P = .007). Whole-body noradrenaline spillover rate correlated with LVMI in the T2D subgroup (r = 0.47, P = .03). In the pooled cohort, LVMI was independently predicted by pulse pressure (r = 0.38, P = .004) and E/A ratio by 2-hour glucose (r = -0.38, P = .005). CONCLUSIONS: Transition from IGT to T2D is associated with cardiac enlargement and diastolic dysfunction, which relate to metabolic, hemodynamic, and SNS alterations.