Biology subjects

Phillips, C. D.

Publications and source records attributed to Phillips, C. D..

3 recordsLinked to original sources

bioRxiv2026

Functional interactions between anteroventral periventricular kisspeptin neurons and gonadotropin-releasing hormone neurons in female mice

Kisspeptin neurons in the rostral hypothalamus are hypothesized to initiate preovulatory gonadotropin-releasing hormone (GnRH) surges by causing estradiol-dependent activation of GnRH neuron action potential firing and subsequent GnRH release. To determine if estradiol or ovarian cycle stage modulates functional connectivity in this circuit, we used optogenetics to photostimulate anteroventral-periventricular (AVPV) area kisspeptin neurons while recording electrical activity and/or evoked synaptic currents from preoptic area GnRH neurons in acutely-prepared mouse brain slices. Slices were prepared from mice in multiple hormonal states, including 2-days post ovariectomy (OVX) and OVX plus estradiol during the morning or afternoon, diestrus, proestrus and 1-week post OVX, and 6-weeks post OVX with or without 1 week of estradiol replacement. Photostimulation induced a sustained, frequency-dependent increase in GnRH neuron firing rate. This neuromodulatory-typical response was not different in diestrous vs proestrous mice but was blunted in 1-week OVX mice, suggesting ovarian steroids amplify this response. Neuromodulatory responses were infrequent in 6-week OVX mice even with 1-week of estradiol treatment. A minority of GnRH neurons exhibited a substantial and near-immediate increase in firing rate typical of fast synaptic transmission. Monosynaptic connectivity was low and stable across the hormone states tested and mediated by GABA. Interestingly, evidence of a monosynaptic connection was not a requirement for GnRH neurons to exhibit a sustained increase in firing rate, suggesting non-synaptic or volume transmission occurs in this system. Synaptic connectivity did, however, amplify the increase in firing rate observed in GnRH neurons from proestrous mice, indicating proestrous hormonal conditions can amplify this response. Significance statementOvulation is initiated by central positive feedback effects of estradiol stimulating a surge of gonadotropin-releasing hormone (GnRH) release. Estradiol feedback is conveyed to GnRH neurons by afferents expressing estrogen receptor alpha, including kisspeptin-expressing neurons in the anteroventral periventricular (AVPV) area. To determine if endocrine milieu modulates functional interactions between AVPV kisspeptin and GnRH neurons, optogenetics was used to stimulate AVPV kisspeptin neurons while recording GnRH neuron spiking activity or synaptic currents in brain slices from ovariectomized, estradiol-treated, and ovary-intact mice. Stimulation (20Hz) increased GnRH neuron firing rate in all hormone conditions. This effect was stronger during proestrus and was further increased in GnRH neurons receiving fast-synaptic transmission. A synaptic connection was not required, however, suggesting volume transmission occurs.

neuroscience↗

bioRxiv2024

Striatal dopamine contributions to skilled motor learning

Coordinated multi-joint limb and digit movements - "manual dexterity" - underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinsons Disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that cortico-striatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release as mice learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In dorsolateral striatum, dopamine dynamics are faster than in dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

neuroscience↗

bioRxiv2018

Metagenomic sequencing provides insights into the location of microbial detoxification in the gut of a small mammalian herbivore

Microbial detoxification of plant defense compounds influences the use of certain plants as food sources by herbivores. The location of microbial detoxification along the gut could have profound influences on the distribution, metabolism, and tolerance to toxic compounds. Stephens woodrats (Neotoma stephensi) specialize on juniper, which is heavily defended by numerous defensive compounds, such as oxalate, phenolics, and monoterpenes. Woodrats maintain two gut chambers harboring dense microbial communities: a foregut chamber proximal to the major site of toxin absorption, and a cecal chamber in their hindgut. We performed several experiments to investigate the location of microbial detoxification in the woodrat gut. First, we measured levels of toxins across gut chambers. Compared to food material, oxalate concentrations were immediately lower in the foregut chamber, while concentrations of terpenes remain high in the foregut, and are lowest in the cecal chamber. We also conducted metagenomic sequencing of the foregut and cecal chambers to compare microbial functions. We found that the majority of genes associated with detoxification functions were more abundant in the cecal chamber. However, some genes associated with degradation of oxalate and phenolic compounds were more abundant in the foregut. Thus, it seems that microbial detoxification may take place in various chambers depending on the class of chemical compound. We hypothesize that the location of microbial detoxification could impact the tolerance of animals to these compounds, which may have ecological and evolutionary consequences.

microbiology↗