Effects of exercise on the sleep microarchitecture in the aging brain: A study on a sedentary sample.

Having a healthy sleep pattern plays a vital role in one's overall health. Sleep in the elderly is characterized by decreased slow-wave sleep and an increase of REM sleep. Furthermore, quantitative electroencephalographic (qEEG) studies have shown an age-related attenuation of total EEG power in sleep. However, exercise has been shown to improve sleep across all age groups. In this study, we used the Sleep Profiler™ EEG Sleep Monitor to observe EEG changes occurring during sleep following an aerobic exercise intervention. This study was done on older adults (N = 18, with only five subjects containing both pre- and post-data of sufficient quality for analysis) with an age range 60-85 years. The aerobics regimen was performed three times weekly for 12-weeks commencing with 20-min sessions. The time of each session progressed by 1-2 min/session as needed to a maximum time of 45 min per session. The macro-architecture (sleep stages) and microarchitecture (EEG) results were analyzed using MATLAB. For the microarchitecture, our results showed more deep sleep following the aerobic exercise regimen. Furthermore, for the microarchitecture, out results shows an increase in total EEG power post-exercise in both light (N1 and L1) and deep sleep (N2 and N3). These preliminary changes in sleep the microarchitecture suggest that non-pharmacologic methods might mitigate age-related EEG changes with potential implications for neurocognitive health.

Phosphodiesterase 9 inhibition prolongs the antiparkinsonian action of l-DOPA in parkinsonian non-human primates.

Phosphodiesterase 9 (PDE9) degrades selectively the second messenger cGMP, which is an important molecule of dopamine signaling pathways in striatal projection neurons (SPNs). In this study, we assessed the effects of a selective PDE9 inhibitor (PDE9i) in the primate model of Parkinson's disease (PD). Six macaques with advanced parkinsonism were used in the study. PDE9i was administered as monotherapy and co-administration with l-DOPA at two predetermined doses (suboptimal and threshold s.c. doses of l-Dopa methyl ester plus benserazide) using a controlled blinded protocol to assess motor disability, l-DOPA -induced dyskinesias (LID), and other neurologic drug effects. While PDE9i was ineffective as monotherapy, 2.5 and 5 mg/kg (s.c.) of PDE9i significantly potentiated the antiparkinsonian effects of l-DOPA with a clear prolongation of the "on" state (p < 0.01) induced by either the suboptimal or threshold l-DOPA dose. Co-administration of PDE9i had no interaction with l-DOPA pharmacokinetics. PDE9i did not affect the intensity of LID. These results indicate that cGMP upregulation interacts with dopamine signaling to enhance the l-DOPA reversal of parkinsonian motor disability. Therefore, striatal PDE9 inhibition may be further explored as a strategy to improve motor responses to l-DOPA in PD.

Prehabilitative exercise hastens recovery from isoflurane in diabetic and non-diabetic rats.

Diabetes has been demonstrated to be one of the strongest predictors of risk for postoperative delirium and functional decline in older patients undergoing surgery. Exercise is often prescribed as a treatment for diabetic patients and regular physical activity is hypothesized to decrease the risk of postoperative cognitive impairments. Prior studies suggest that anesthetic emergence trajectories and recovery are predictive of risk for later postoperative cognitive impairments. Therapeutic strategies aimed at improving emergence and recovery from anesthesia may therefore be beneficial for diabetic patients. Wistar (n = 32) and Goto-Kakizaki (GK) type 2 diabetic (n = 32) rats between 3-4 months old underwent treadmill exercise for 30 min/day for ten days or remained inactive. Pre-anesthesia spontaneous alternation behavior was recorded with a Y-maze. Rats then received a 2-h exposure to 1.5-2 % isoflurane or oxygen only. The time to reach anesthetic emergence and post-anesthesia recovery behaviors was recorded for each rat. Postsynaptic density protein-95 (PSD-95), an important scaffolding protein required for synaptic plasticity, protein levels were quantified from hippocampus using western blot. Spontaneous alternation behavior (p = 0.044) and arm entries (p < 0.001) were decreased in GK rats. There was no difference between groups in emergence times from isoflurane, but exercise hastened the recovery time (p = 0.008) for both Wistar and GK rats. Following 10 days of exercise, both Wistar and GK rats show increased levels of PSD-95 in the hippocampus. Prehabilitation with moderate intensity exercise, even on a short timescale, is beneficial for recovery from isoflurane in rats, regardless of metabolic disease status.

Sleep/Wake Behavior and EEG Signatures of the TgF344-AD Rat Model at the Prodromal Stage.

Transgenic modification of the two most common genes (APPsw, PS1ΔE9) related to familial Alzheimer's disease (AD) in rats has produced a rodent model that develops pathognomonic signs of AD without genetic tau-protein modification. We used 17-month-old AD rats (n = 8) and age-matched controls (AC, n = 7) to evaluate differences in sleep behavior and EEG features during wakefulness (WAKE), non-rapid eye movement sleep (NREM), and rapid eye movement sleep (REM) over 24-h EEG recording (12:12h dark-light cycle). We discovered that AD rats had more sleep-wake transitions and an increased probability of shorter REM and NREM bouts. AD rats also expressed a more uniform distribution of the relative spectral power. Through analysis of information content in the EEG using entropy of difference, AD animals demonstrated less EEG information during WAKE, but more information during NREM. This seems to indicate a limited range of changes in EEG activity that could be caused by an AD-induced change in inhibitory network function as reflected by increased GABAAR-ß2 expression but no increase in GAD-67 in AD animals. In conclusion, this transgenic rat model of Alzheimer's disease demonstrates less obvious EEG features of WAKE during wakefulness and less canonical features of sleep during sleep.

Optical suppression of drug-evoked phasic dopamine release.

Brief fluctuations in dopamine concentration (dopamine transients) play a key role in behavior towards rewards, including drugs of abuse. Drug-evoked dopamine transients may result from actions at both dopamine cell bodies and dopamine terminals. Inhibitory opsins can be targeted to dopamine neurons permitting their firing activity to be suppressed. However, as dopamine transients can become uncoupled from firing, it is unknown whether optogenetic hyperpolarization at the level of the soma is able to suppress dopamine transients. Here, we used in vivo fast-scan cyclic voltammetry to record transients evoked by cocaine and raclopride in nucleus accumbens (NAc) of urethane-anesthetized rats. We targeted halorhodopsin (NpHR) specifically to dopamine cells by injecting Cre-inducible virus into ventral tegmental area (VTA) of transgenic rats that expressed Cre recombinase under control of the tyrosine hydroxylase promoter (TH-Cre(+) rats). Consistent with previous work, co-administration of cocaine and raclopride led to the generation of dopamine transients in NAc shell. Illumination of VTA with laser strongly suppressed the frequency of transients in NpHR-expressing rats, but not in control rats. Laser did not have any effect on amplitude of transients. Thus, optogenetics can effectively reduce the occurrence of drug-evoked transients and is therefore a suitable approach for studying the functional role of such transients in drug-associated behavior.

Glucagon-like peptide-1 receptor activation in the nucleus accumbens core suppresses feeding by increasing glutamatergic AMPA/kainate signaling.

Glucagon-like peptide-1 receptor (GLP-1R) activation in the nucleus accumbens (NAc) core is pharmacologically and physiologically relevant for regulating palatable food intake. Here, we assess whether GLP-1R signaling in the NAc core of rats modulates GABAergic medium spiny neurons (MSNs) through presynaptic-glutamatergic and/or presynaptic-dopaminergic signaling to control feeding. First, ex vivo fast-scan cyclic voltammetry showed that the GLP-1R agonist exendin-4 (Ex-4) does not alter dopamine release in the NAc core. Instead, support for a glutamatergic mechanism was provided by ex vivo electrophysiological analyses showing that Ex-4 activates presynaptic GLP-1Rs in the NAc core to increase the activity of MSNs via a glutamatergic, AMPA/kainate receptor-mediated mechanism, indicated by increased mEPSC frequency and decreased paired pulse ratio in core MSNs. Only a small, direct excitatory effect on MSNs by Ex-4 was observed, suggesting that the contribution of postsynaptic GLP-1R to MSN activity is minimal. The behavioral relevance of the electrophysiological data was confirmed by the finding that intracore injection of the AMPA/kainate receptor antagonist CNQX attenuated the ability of NAc core GLP-1R activation by Ex-4 microinjection to suppress food intake and body weight gain; in contrast, intracore NMDA receptor blockade by AP-5 did not inhibit the energy balance effects of NAc core Ex-4. Together, these data provide evidence for a novel glutamatergic, but not dopaminergic, mechanism by which NAc core GLP-1Rs promote negative energy balance.