Inhibition of Astrocytic Histamine N-Methyltransferase as a Possible Target for the Treatment of Alzheimer’s Disease

Alzheimer’s disease (AD) represents the principal cause of dementia among the elderly. Great efforts have been established to understand the physiopathology of AD. Changes in neurotransmitter systems in patients with AD, including cholinergic, GABAergic, serotoninergic, noradrenergic, and histaminergic changes have been reported. Interestingly, changes in the histaminergic system have been related to cognitive impairment in AD patients. The principal pathological changes in the brains of AD patients, related to the histaminergic system, are neurofibrillary degeneration of the tuberomammillary nucleus, the main source of histamine in the brain, low histamine levels, and altered signaling of its receptors. The increase of histamine levels can be achieved by inhibiting its degrading enzyme, histamine N-methyltransferase (HNMT), a cytoplasmatic enzyme located in astrocytes. Thus, increasing histamine levels could be employed in AD patients as co-therapy due to their effects on cognitive functions, neuroplasticity, neuronal survival, neurogenesis, and the degradation of amyloid beta (Aβ) peptides. In this sense, the evaluation of the impact of HNMT inhibitors on animal models of AD would be interesting, consequently highlighting its relevance.

The retinal ipRGC-preoptic circuit mediates the acute effect of light on sleep

Light regulates daily sleep rhythms by a neural circuit that connects intrinsically photosensitive retinal ganglion cells (ipRGCs) to the circadian pacemaker, the suprachiasmatic nucleus. Light, however, also acutely affects sleep in a circadian-independent manner. The neural circuits involving the acute effect of light on sleep remain unknown. Here we uncovered a neural circuit that drives this acute light response, independent of the suprachiasmatic nucleus, but still through ipRGCs. We show that ipRGCs substantially innervate the preoptic area (POA) to mediate the acute light effect on sleep in mice. Consistently, activation of either the POA projecting ipRGCs or the light-responsive POA neurons increased non-rapid eye movement (NREM) sleep without influencing REM sleep. In addition, inhibition of the light-responsive POA neurons blocked the acute light effects on NREM sleep. The predominant light-responsive POA neurons that receive ipRGC input belong to the corticotropin-releasing hormone subpopulation. Remarkably, the light-responsive POA neurons are inhibitory and project to well-known wakefulness-promoting brain regions, such as the tuberomammillary nucleus and the lateral hypothalamus. Therefore, activation of the ipRGC-POA circuit inhibits arousal brain regions to drive light-induced NREM sleep. Our findings reveal a functional retina-brain circuit that is both necessary and sufficient for the acute effect of light on sleep.

The role of the central histaminergic system in emergence from propofol anesthesia

Background: The mechanisms of emergence from general anesthesia remain to be elucidated. Recent studies indicate that the central histaminergic system plays a critical role in maintaining wakefulness. Methods: Role of the central histaminergic system in emergence from propofol anesthesia using microinjections and single-unit recordings in rats was evaluated. Results: Intracerebroventricular (icv) microinjections of histamine decreased the emergence time in a dose-dependent manner and had an excitatory effect on the firing activity of medial prefrontal cortex (mPFC) neurons, while the decrease of emergence time was completely reversed by the pre-treatment with triprolidine (80 μg/5 μl) but not cimetidine (100 μg/5 μl). Moreover, the presumed histaminergic neurons fired in a state-dependent manner, and there was a dramatic increase in firing activity before regain of righting reflex. Furthermore, bidirectional manipulations of emergence were achieved through the microinjection of GABA (10 μg/side) and a potent H3 receptor inverse agonist ciproxian (1 μg/side) into the posterior hypothalamus, where the tuberomammillary nucleus (TMN) resides. Conclusion: Combining the behavioral and neurophysiologic evidence, the central histaminergic system promotes emergence from propofol anesthesia in rats. Our findings suggest an important role of the central histaminergic system in a broader field of state transitions, such as emergence from propofol anesthesia.

Chemogenetic modulation of histaminergic neurons in the tuberomammillary nucleus alters territorial aggression and wakefulness

Designer receptor activated by designer drugs (DREADDs) techniques are widely used to modulate the activities of specific neuronal populations during behavioural tasks. However, DREADDs-induced modulation of histaminergic neurons in the tuberomammillary nucleus (HATMN neurons) has produced inconsistent effects on the sleep–wake cycle, possibly due to the use of Hdc-Cre mice driving Cre recombinase and DREADDs activity outside the targeted region. Moreover, previous DREADDs studies have not examined locomotor activity and aggressive behaviours, which are also regulated by brain histamine levels. In the present study, we investigated the effects of HATMN activation and inhibition on the locomotor activity, aggressive behaviours and sleep–wake cycle of Hdc-Cre mice with minimal non-target expression of Cre-recombinase. Chemoactivation of HATMN moderately enhanced locomotor activity in a novel open field. Activation of HATMN neurons significantly enhanced aggressive behaviour in the resident–intruder test. Wakefulness was increased and non-rapid eye movement (NREM) sleep decreased for an hour by HATMN chemoactivation. Conversely HATMN chemoinhibition decreased wakefulness and increased NREM sleep for 6 hours. These changes in wakefulness induced by HATMN modulation were related to vigilance status transition. These results indicate the influences of HATMN neurons on exploratory activity, territorial aggression, and wake maintenance.

The Interaction Between the Ventrolateral Preoptic Nucleus and the Tuberomammillary Nucleus in Regulating the Sleep-Wakefulness Cycle

The ventrolateral preoptic nucleus (VLPO) in the anterior hypothalamus and the tuberomammillary nucleus (TMN) in the posterior hypothalamus are critical regions which involve the regulation of sleep-wakefulness flip-flop in the central nervous system. Most of the VLPO neurons are sleep-promoting neurons, which co-express γ-aminobutyric acid (GABA) and galanin, while TMN neurons express histamine (HA), a key wake-promoting neurotransmitter. Previous studies have shown that the two regions are innervated between each other, but how to regulate the sleep-wake cycle are not yet clear. Here, bicuculline (Bic), a GABAA-receptor antagonist, L-glutamate (L-Glu), an excitatory neurotransmitter, and triprolidine (Trip), a HA1 receptor (HRH1) inhibitor, were bilaterally microinjected into TMN or VLPO after surgically implanting the electroencephalogram (EEG) and electromyography (EMG) electrode recording system. Microinjecting L-Glu into VLPO during the night significantly increased the NREM sleep time, and this phenomenon was weakened after selectively blocking GABAA receptors with Bic microinjected into TMN. Those results reveal that VLPO neurons activated, which may inhibit TMN neurons inducing sleep via GABAA receptors. On the contrary, exciting TMN neurons by L-Glu during the day, the wakefulness time was significantly increased. These phenomena were reversed by blocking HRH1 with Trip microinjected into VLPO. Those results reveal that TMN neuron activating may manipulate VLPO neurons via HRH1, and induce wakefulness. In conclusion, VLPO GABAergic neurons and TMN histaminergic neurons may interact with each other in regulating the sleep-wake cycle.

0076 The Role of Preoptic Area GABAergic Axonal Projections to Tuberomammillary Nucleus in Sleep Homeostasis

Introduction Sleep deprivation has profound widespread physiological effects including cognitive impairment, compromised immune system function and increased risk of cardiovascular disease. The preoptic area (POA) of the hypothalamus contains sleep-active GABAergic neurons that respond to sleep homeostasis. We have shown that activation of POA GABAergic axons innervating the tuberomammillary nucleus (TMN, GABAergicPOA ->TMN) are critical for sleep regulation but it is unknown if these projections modulate sleep homeostasis. Methods To monitor in vivo neural activity of GABAergicPOA ->TMN projection neurons during sleep deprivation and rebound, fiber photometry was used. GAD2-Cre mice (n=6) were injected with AAV-DIO-GCaMP6S into the POA and an optic fiber was implanted into the TMN. An electroencephalogram (EEG) and electromyography (EMG) implant was mounted upon the skull to identify brain states. Calcium activity was measured for six hours starting at ZT4. Each mouse was recorded for three days to establish baseline sleep calcium activity with at least two days between sessions. During sleep deprivation sessions, an experimenter sleep deprived each mouse starting at ZT0 for six hours by gently brushing the animal with a small paintbrush to maintain wakefulness and minimize the stress to the animal. Results During baseline sleep recordings, GABAergicPOA ->TMN projection neurons are most active during sleep (NREM and REM) which is maintained until wake onset. As sleep pressure increases, GABAergicPOA ->TMN projection neurons display gradual increase in neural activity compared to time-matched points during baseline sleep recordings. Once mice were permitted to enter sleep rebound, GABAergicPOA ->TMN projection neurons gradually displayed decreased activity as sleep pressure eased. Conclusion GABAergicPOA ->TMN projection neurons show a strong increase in activity to drive homeostatic sleep need during periods of increased sleep pressure but subside once this pressure is reduced. Support This work is supported by NIH grant R01-NS-110865.