Biology subjects

Fisher, S. D.

Publications and source records attributed to Fisher, S. D..

4 recordsLinked to original sources

bioRxiv2023

Optogenetic recruitment of hypothalamic corticotrophin-releasing-hormone (CRH) neurons reduces motivational drive

Impaired motivational drive is a key feature of depression. Chronic stress is a known antecedent to the development of depression in humans and depressive-like states in animals. Whilst there is a clear relationship between stress and motivational drive, the mechanisms underpinning this association remain unclear. One hypothesis is that the endocrine system, via corticotropin-releasing hormone (CRH) in the paraventricular nucleus of the hypothalamus (PVN; PVNCRH), initiates a hormonal cascade resulting in glucocorticoid release, and that excessive glucocorticoids change brain circuit function to produce depression-related symptoms. Another, mostly unexplored hypothesis is that the direct activity of PVNCRH neurons and their input to other stress- and reward-related brain regions drives these behaviours. To further understand the direct involvement of PVNCRH neurons in motivation, we used optogenetic stimulation to activate these neurons one hour/day for 5 consecutive days and showed increased acute stress-related behaviours and long-lasting deficits in the motivational drive for sucrose. This was associated with increased Fos-protein expression in the lateral hypothalamus (LH). Direct stimulation of the PVNCRH inputs in the LH produced a similar pattern of effects on sucrose motivation. Together, these data suggest that PVNCRH neuronal activity may be directly responsible for changes in motivational drive and that these behavioural changes may, in part, be driven by PVNCRH synaptic projections to the LH.

neuroscience↗

bioRxiv2023

A hierarchical pathway for assembly of the distal appendages that organize primary cilia

Distal appendages are nine-fold symmetric blade-like structures attached to the distal end of the mother centriole. These structures are critical for formation of the primary cilium, by regulating at least four critical steps: ciliary vesicle recruitment, recruitment and initiation of intraflagellar transport (IFT), and removal of CP110. While specific proteins that localize to the distal appendages have been identified, how exactly each protein functions to achieve the multiple roles of the distal appendages is poorly understood. Here we comprehensively analyze known and newly discovered distal appendage proteins (CEP83, SCLT1, CEP164, TTBK2, FBF1, CEP89, KIZ, ANKRD26, PIDD1, LRRC45, NCS1, C3ORF14) for their precise localization, order of recruitment, and their roles in each step of cilia formation. Using CRISPR-Cas9 knockouts, we show that the order of the recruitment of the distal appendage proteins is highly interconnected and a more complex hierarchy. Our analysis highlights two protein modules, CEP83-SCLT1 and CEP164-TTBK2, as critical for structural assembly of distal appendages. Functional assay revealed that CEP89 selectively functions in RAB34+ ciliary vesicle recruitment, while deletion of the integral components, CEP83-SCLT1-CEP164-TTBK2, severely compromised all four steps of cilium formation. Collectively, our analyses provide a more comprehensive view of the organization and the function of the distal appendage, paving the way for molecular understanding of ciliary assembly.

cell biology↗

bioRxiv2020

A ventral striatal-orexin/hypocretin circuit modulates approach but not consumption of food.

Reward-seeking involves the engagement and computation of multiple physiological and motivational parameters. The lateral hypothalamus (LH) is a necessary node in the circuits that control food-seeking and motivation. One group of cells that plays an important yet incompletely understood role in these processes are the orexin/hypocretin (OX/HT) neurons. OX/HT cells are located exclusively within the LH and are implicated in feeding, arousal, and reward-seeking behavior. Importantly, the role of OX/HT neurons in consummatory versus reward-seeking actions is not fully defined, nor are the circuits that control the activity of these neurons under different behavioral states. Here we show that OX/HT neurons respond in real time to food presentation and that this response is modulated by differences in metabolic state. We observed increased OX/HT neuron activity on approach to food, but this activity trended towards pre-approach levels by the start of the consummatory phase. Next, we studied ventrostriatopallidal (VSP) inputs to the OX/HT neurons. Using optogenetics and cell type-specific electrophysiology, we found that ventral pallidum inputs onto OX/HT neurons exert strong inhibitory (and weak excitatory) effects whereas the lateral nucleus accumbens shell provides weaker direct inhibitory connections with OX/HT neurons. These findings reveal that the activity of OX/HT neurons is strongly modulated by metabolic and hedonic state. Further, OX/HT neurons is primarily associated with food approach and that the effect of VSP-terminal output is to suppress OX/HT activity.

neuroscience↗

bioRxiv2019

Coincidence of cholinergic pauses, dopaminergic activation and depolarization drives synaptic plasticity in the striatum

Pauses in the firing of tonically-active cholinergic interneurons (ChIs) in the striatum coincide with phasic activation of dopamine neurons during reinforcement learning. However, how this pause influences cellular substrates of learning is unclear. Using two in vivo paradigms, we report that long-term potentiation (LTP) at corticostriatal synapses with spiny projection neurons (SPNs) is dependent on the temporal coincidence of ChI pause and dopamine phasic activation, critically accompanied by SPN depolarization.

neuroscience↗