Biology subjects

Mohammadkhani, A.

Publications and source records attributed to Mohammadkhani, A..

3 recordsLinked to original sources

bioRxiv2025

Brain serotonin circuit reverses decline in physical activity with age

Physical inactivity increases with age and is the fourth leading risk factor for mortality. Establishing the mechanisms underpinning declining physical activity (PA) with age has remained both elusive and difficult to overcome. Older (50-70 years old) compared with younger (17-30 years old) UK participants showed reduced PA, and this profile was effectively modelled in mice. Analysis of brain serotonin (5-HT) neurons in the dorsal raphe (DR) revealed altered firing activity in older mice. Chemogenetically mimicking this 5-HTDR tone in young adult mice produced an older adult PA profile. Genetically blocking 5-HT activity at 5-HT2C receptors (5-HT2CRs) prevented the decline in PA with age. Importantly, barring 5-HT action at 5-HT2CRs specifically within the ventral tegmental area restored youthful PA levels and strength in older mice. These data fill a longstanding knowledge gap by defining brain circuitry programming the decline in PA with age, and importantly, a means to reverse it.

neuroscience↗

bioRxiv2024

Distinct neuromodulatory effects of endogenous orexin and dynorphin corelease on projection-defined ventral tegmental dopamine neurons.

AbstractDopamine (DA) neurons in the ventral tegmental area (VTA) respond to motivationally relevant cues and circuit-specific signaling drives different aspects of motivated behavior. Orexins (ox; also known as hypocretin) and dynorphin (dyn) are co-expressed lateral hypothalamic (LH) neuropeptides that project to the VTA. These peptides have opposing effects on the firing activity of VTADA neurons via orexin 1 (Ox1R) or kappa opioid (KOR) receptors, respectively. Given that Ox1R activation increases VTADA firing, and KOR decreases firing, it is unclear how the co-released peptides contribute to the net activity of DA neurons. We tested if optical stimulation of LH neuromodulates VTADA neuronal activity via peptide release and if the effects of optically driven LHox/dyn release segregates based on VTADA projection targets including the basolateral amygdala (BLA) or the lateral or medial shell of the nucleus accumbens (lAcbSh, mAchSh). Using a combination of circuit tracing, optogenetics, and patch clamp electrophysiology in male and female orexincre mice we showed a diverse response of LH optical stimulation on VTADA neuronal firing, that are not mediated by fast transmitter release and are blocked by antagonists to KOR and Ox1R signaling. Additionally, where optical stimulation of LHox/dyn inputs in the VTA inhibited firing of the majority of BLA projecting VTADA neurons, optical stimulation of LH inputs in the VTA bidirectionally affects firing of either lAcbSh or mAchSh projecting VTADA neurons. These findings indicate that LHox/dyn corelease may influence the output of the VTA by balancing ensembles of neurons within each population which contribute to different aspects of reward seeking. Significance StatementThe mesolimbic dopamine (DA) system is known to play a crucial role in motivation and reward-learning and receives neuromodulatory input from the lateral hypothalamus (LH). We show that optical stimulation of the orexin-containing LH input in the VTA releases both orexin and dynorphin to bidirectionally alter VTADA firing. Furthermore, orexin and dynorphin differentially modulate firing of DA inputs to the basolateral amygdala, whereby dynorphin predominates, or to the nucleus accumbens which is sensitive to both neuromodulators. Our findings contribute to a more comprehensive understanding of the neuromodulatory effects of coreleased LH orexin and dynorphin on the VTADA system.

neuroscience↗

bioRxiv2019

Persistent effects of the orexin-1 receptor antagonist SB-334867 on motivation for the fast acting opioid remifentanil

The orexin (hypocretin) system is important for reward-seeking behavior. The orexin-1 receptor (Ox1R) antagonist SB334867 (SB) reduces seeking of food and drug reward under conditions of high motivation. There is some evidence that the effects of systemic SB on reward seeking persist beyond the pharmacological availability of the drug, however the time course of these effects is not well characterized, nor is it known whether similar persistent effects are observed following intraparenchymal injections. Here, we used a behavioral economics paradigm, which allows for repeated testing of drug motivation across consecutive days, to examine the persistent effects of acute systemic and local treatment with SB on motivation for the short-acting opioid remifentanil. Systemic injections of SB immediately prior to behavioral testing reduced motivation for remifentanil; this effect was sustained on a subsequent test at 24h, but not on a third test at 48h. When injected locally into caudal ventral pallidum (cVP) the effects of SB were more persistent, with reduced motivation observed for up to 48h. We next made SB injections into cVP 24h prior to behavioral testing; this produced persistent effects that persisted for at least 72h post-treatment. Cued reinstatement of extinguished remifentanil seeking was also attenuated by pretreatment with SB 24h prior. These data indicate that the effects of SB on opioid seeking behavior persist beyond the bioavailability of the compound. These observations might have important ramifications for the future clinical use of orexin receptor antagonists for the treatment of addiction.

animal behavior and cognition↗