J147 affects cognition and anxiety after surgery in Zucker rats.

Vulnerable patients are at risk for neuroinflammation-mediated post-operative complications, including depression (POD) and cognitive dysfunction (POCD). Zucker rats, expressing multiple risk factors for post-operative complications in humans, may provide a clinically relevant model to study pathophysiology and explore potential interventions. J147, a newly developed anti-dementia drug, was shown to prevent POCD in young healthy rats, and improved early post-surgical recovery in Zucker rats. Aim of the present study was to investigate POCD and the therapeutic potential of J147 in male Zucker rats. Risk factors in the Zucker rat strain were evaluated by comparison with lean littermates. Zucker rats were subjected to major abdominal surgery. Acute J147 treatment was provided by a single iv injection (10 mg/kg) at the start of surgery, while chronic J147 treatment was provided in the food (aimed at 30 mg/kg/day), starting one week before surgery and up to end of protocol. Effects on behavior were assessed, and plasma, urine and brain tissue were collected and processed for immunohistochemistry and molecular analyses. Indeed, Zucker rats displayed increased risk factors for POCD, including obesity, high plasma triglycerides, low grade systemic inflammation, impaired spatial learning and decreased neurogenesis. Surgery in Zucker rats reduced exploration and increased anxiety in the Open Field test, impaired short-term spatial memory, induced a shift in circadian rhythm and increased plasma neutrophil gelatinase-associated lipocalin (NGAL), microglia activity in the CA1 and blood brain barrier leakage. Chronic, but not acute J147 treatment reduced anxiety in the Open Field test and protected against the spatial memory decline. Moreover, chronic J147 increased glucose sensitivity. Acute J147 treatment improved long-term spatial memory and reversed the circadian rhythm shift. No anti-inflammatory effects were seen for J147. Although Zucker rats displayed risk factors, surgery did not induce extensive POCD. However, increased anxiety may indicate POD. Treatment with J147 showed positive effects on behavioral and metabolic parameters, but did not affect (neuro)inflammation. The mixed effect of acute and chronic treatment may suggest a combination for optimal treatment.

Bright Light Increases Alertness and Not Cortisol in Healthy Men: A Forced Desynchrony Study Under Dim and Bright Light (I).

Light-induced improvements in alertness are more prominent during nighttime than during the day, suggesting that alerting effects of light may depend on internal clock time or wake duration. Relative contributions of both factors can be quantified using a forced desynchrony (FD) designs. FD designs have only been conducted under dim light conditions (<10 lux) since light above this amount can induce non-uniform phase progression of the circadian pacemaker (also called relative coordination). This complicates the mathematical separation of circadian clock phase from homeostatic sleep pressure effects. Here we investigate alerting effects of light in a novel 4 × 18 h FD protocol (5 h sleep, 13 h wake) under dim (6 lux) and bright light (1300 lux) conditions. Hourly saliva samples (melatonin and cortisol assessment) and 2-hourly test sessions were used to assess effects of bright light on subjective and objective alertness (electroencephalography and performance). Results reveal (1) stable free-running cortisol rhythms with uniform phase progression under both light conditions, suggesting that FD designs can be conducted under bright light conditions (1300 lux), (2) subjective alerting effects of light depend on elapsed time awake but not circadian clock phase, while (3) light consistently improves objective alertness independent of time awake or circadian clock phase. Reconstructing the daily time course by combining circadian clock phase and wake duration effects indicates that performance is improved during daytime, while subjective alertness remains unchanged. This suggests that high-intensity indoor lighting during the regular day might be beneficial for mental performance, even though this may not be perceived as such.

Bright Light Decreases Peripheral Skin Temperature in Healthy Men: A Forced Desynchrony Study Under Dim and Bright Light (II).

Human thermoregulation is strictly regulated by the preoptic area of the hypothalamus, which is directly influenced by the suprachiasmatic nucleus (SCN). The main input pathway of the SCN is light. Here, thermoregulatory effects of light were assessed in humans in a forced desynchrony (FD) design. The FD experiment was performed in dim light (DL, 6 lux) and bright white light (BL, 1300 lux) in 8 men in a semi-randomized within-subject design. A 4 × 18 h FD protocol (5 h sleep, 13 h wake) was applied, with continuous core body temperature (CBT) and skin temperature measurements at the forehead, clavicles, navel, palms, foot soles and toes. Skin temperature parameters indicated sleep-wake modulations as well as internal clock variations. All distal skin temperature parameters increased during sleep, when CBT decreased. Light significantly affected temperature levels during the wake phase, with decreased temperature measured at the forehead and toes and increased navel and clavicular skin temperatures. These effects persisted when the lights were turned off for sleep. Circadian amplitude of CBT and all skin temperature parameters decreased significantly during BL exposure. Circadian proximal skin temperatures cycled in phase with CBT, while distal skin temperatures cycled in anti-phase, confirming the idea that distal skin regions reflect heat dissipation and proximal regions approximate CBT. In general, we find that increased light intensity exposure may have decreased heat loss in humans, especially at times when the circadian system promotes sleep.

Bright Light During Wakefulness Improves Sleep Quality in Healthy Men: A Forced Desynchrony Study Under Dim and Bright Light (III).

Under real-life conditions, increased light exposure during wakefulness seems associated with improved sleep quality, quantified as reduced time awake during bed time, increased time spent in non-rapid eye movement (NREM) sleep, or increased power of the electroencephalogram delta band (0.5-4 Hz). The causality of these important relationships and their dependency on circadian phase and/or time awake has not been studied in depth. To disentangle possible circadian and homeostatic interactions, we employed a forced desynchrony protocol under dim light (6 lux) and under bright light (1300 lux) during wakefulness. Our protocol consisted of a fast cycling sleep-wake schedule (13 h wakefulness-5 h sleep; 4 cycles), followed by 3 h recovery sleep in a within-subject cross-over design. Individuals (8 men) were equipped with 10 polysomnography electrodes. Subjective sleep quality was measured immediately after wakening with a questionnaire. Results indicated that circadian variation in delta power was only detected under dim light. Circadian variation in time in rapid eye movement (REM) sleep and wakefulness were uninfluenced by light. Prior light exposure increased accumulation of delta power and time in NREM sleep, while it decreased wakefulness, especially during the circadian wake phase (biological day). Subjective sleep quality scores showed that participants rated their sleep quality better after bright light exposure while sleeping when the circadian system promoted wakefulness. These results suggest that high environmental light intensity either increases sleep pressure buildup during wakefulness or prevents the occurrence of micro-sleep, leading to improved quality of subsequent sleep.