Biology subjects

McIntyre, C.

Publications and source records attributed to McIntyre, C..

9 recordsLinked to original sources

bioRxiv2026

Different hippocampal subfield volumes predict source memory performance and general cognitive ability in an adult lifespan sample

Modest positive associations between episodic memory performance and whole hippocampal and hippocampal subfield volumes have been reported in numerous prior studies. A smaller number of studies have reported associations between hippocampal volume and performance on tests of non-mnemonic cognition. The present study examined whether these associations were evident in a lifespan sample of cognitively healthy adults. Of particular interest was whether any identified associations were sensitive to age, and whether associations between subfield volumes and mnemonic and non-mnemonic performance were subfield dependent. We acquired high-resolution T1- and T2-weighted structural images from 163 adults (18-87 years of age). Participants also undertook a comprehensive neuropsychological test battery and an in-scanner test of source memory. Principal components analysis was employed to reduce the neuropsychological test scores to 5 cognitive components. Two components reflected memory performance while the other three reflected different aspects of non-mnemonic cognition. Hippocampal subfields (Cornu Ammonis (CA)1, CA2-3, dentate gyrus (DG) and subiculum) were segmented and measured with the Automated Segmentation of Hippocampus Subfields (ASHS) package. Source memory performance was selectively associated across participants with CA2-3 volume. By contrast, both mnemonic and non-mnemonic component scores derived from the test battery were associated exclusively with the volume of the DG. All associations were age-invariant. The findings indicate that different cognitive domains can be dissociated by virtue of their associations with different hippocampal subfields. Of importance, these associations appear to be life-long and hence are unlikely to reflect individual differences in age-related decline in structural integrity.

neuroscience↗

bioRxiv2026

Physics-aware measurement-supervised deep learning enables point spread function inversion in soft X-ray tomography

Soft X-ray tomography (SXT) is an emerging modality for whole-cell 3D imaging in near-native states. However, the effective spatial resolution is limited by optical artifacts characterized by the point spread function (PSF). Standard reconstruction methods force a compromise between structural sharpness and noise, failing to fully resolve these depth-dependent artifacts. By embedding experimentally measured, depth-variant PSFs into a differentiable forward model, we demonstrate a physics-aware computational optimization that bypasses these limitations to recover high-frequency cellular ultrastructure. The structural fidelity was validated using split-tilt Fourier ring correlation (FRC), alongside an experimental bead phantom tomogram, providing supporting evidence that the recovered high-frequency features reflect genuine specimen structure rather than fabricated artifacts. Our method effectively increases FRC spatial resolution and recovers cellular ultrastructure. Furthermore, under sparse-angular subsampling, the framework maintained spatial resolution using half the projection angles, a computational proxy pointing toward the potential for reduced radiation exposure in future acquisitions. This hardware-free, computational approach offers a route toward mitigating the optical and dosimetric constraints that currently limit nanoscale soft X-ray tomography.

Cell Biology↗

bioRxiv2026

POLQ-driven repair scars shape the immunogenic landscape of homologous recombination-deficient pancreatic cancer

Pancreatic cancer (PC) is broadly resistant to immune checkpoint blockade, although a subset of homologous recombination-deficient (HRD) tumors exhibits durable immune engagement. The genomic features that distinguish these immune-responsive tumors from immune-inert HRD tumors remain poorly understood. Here we identify a microhomology-mediated end joining (MMEJ) repair scar, the MMEJ Deletion Footprint (MDF), as a genomic readout of POLQ-associated error-prone repair that enriches for frameshift indels. Across the multi-omic discovery cohort integrating tumor genomics, single-nucleus transcriptomics and spatial immune profiling, MDF-high HRD PC exhibited increased frameshift-indel-derived neoantigens and interferon programs. MDF was further associated with remodeling of the myeloid compartment toward MHC II-high dendritic cell-like antigen-presenting macrophage states and the immune synapse architecture marked by increased spatial interaction between APC-like macrophages and cytotoxic CD8+ T cells. These tissue-level features aligned with a functional trajectory shift of CD8+ T cells, consistent with effective anti-tumor immunity and was associated with favorable clinical outcomes of patients. Together, our findings position MMEJ-linked repair scarring as actionable biology that connects an HRD genotype to immune organization and suggests rational immunotherapy combinations that may enhance antigen presentation and myeloid activation to extend durable benefit in HRD-lineage cancers.

cancer biology↗

bioRxiv2025

Selective innervation of subpopulations of striatal neurons by distinct sets of neurons of the external globus pallidus

The striatum, the primary input nucleus of the basal ganglia, contains diverse populations of projection neurons and interneurons, each with distinct roles in motor processing. The external globus pallidus contains distinct populations of inhibitory neurons that are highly interconnected with other regions of the basal ganglia. How pallidal neurons innervate different populations of striatal neurons is critical for our understanding of their role in motor processing. Here we use monosynaptic viral tracing in transgenic mice to quantitively define the organization of pallidostriatal connectivity. We show that FoxP2-expressing arkypallidal neurons provide the greatest input to the striatum, primarily targeting indirect pathway spiny projection neurons and cholinergic interneurons. In contrast, prototypic pallidal neurons, defined by Nkx2-1 expression, preferentially innervate parvalbumin- and somatostatin-expressing interneurons. These data reveal a structured and selective organization of pallidostriatal projections, suggesting that distinct classes of pallidal neurons modulate striatal circuits through complementary pathways. Mapping these connections is key to understanding how basal ganglia networks coordinate motor control.

neuroscience↗

bioRxiv2022

Posterodorsal medial amygdala urocortin-3, GABA and glutamate mediate suppression of LH pulsatility in female mice

The posterodorsal subnucleus of the medial amygdala (MePD) is an upstream modulator of the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes. Inhibition of MePD urocortin-3 (Ucn3) neurons prevents psychological stress-induced suppression of LH pulsatility while blocking the stress-induced elevations in corticosterone (CORT) secretion in female mice. We explore the neurotransmission and neural circuitry suppressing the GnRH pulse generator by MePD Ucn3 neurons and we further investigate whether MePD Ucn3 efferent projections to the PVN control CORT secretion and LH pulsatility. Ucn3-cre-tdTomato female ovariectomised (OVX) mice were unilaterally injected with AAV-ChR2 and implanted with optofluid cannulae targeting the MePD. We optically activated Ucn3 neurons in the MePD with blue light at 10Hz and monitored the effect on LH pulses. Next, we combined optogenetic stimulation of MePD Ucn3 neurons with pharmacological antagonism of GABAA or GABAB receptors with bicuculline or CGP, respectively, as well as a combination of NMDA and AMPA receptor antagonists, AP5 and CNQX respectively, and observed the effect on pulsatile LH secretion. A separate group of Ucn3-cre-tdTomato OVX mice with 17{beta}-estradiol (E2) replacement were unilaterally injected with AAV-ChR2 in the MePD and implanted with fibreoptic cannulae targeting the PVN. We optically stimulated the MePD Ucn3 efferent projections in the PVN with blue light at 20Hz and monitored the effect on CORT secretion and LH pulses. We reveal for the first time that activation of Ucn3 neurons in the MePD inhibits GnRH pulse generator frequency via GABA and glutamate signalling within the MePD, while MePD Ucn3 projections to the PVN modulate the HPG and HPA axes.

neuroscience↗

bioRxiv2021

GnRH pulse generator frequency is modulated by kisspeptin and GABA-glutamate interactions in the posterodorsal medial amygdala in female mice

Kisspeptin neurons in the arcuate nucleus of the hypothalamus generate GnRH pulses, and act as critical initiators of functional gonadotrophin secretion, and reproductive competency. However, kisspeptin in other brain regions, most notably the posterodorsal subnucleus of the medial amygdala (MePD), plays a significant modulatory role over the hypothalamic kisspeptin population; our recent studies using optogenetics have shown that low frequency light stimulation of MePD kisspeptin results in increased LH pulse frequency. Nonetheless, the neurochemical pathways that underpin this regulatory function remain unknown. To study this, we have utilised an optofluid technology, precisely combining optogenetic stimulation with pharmacological receptor antagonism, to investigate the neurotransmission involved in this circuitry. We have shown that functional neurotransmission of both GABAA and glutamate is a requirement for effective modulation of the GnRH pulse generator by amygdala kisspeptin neurons.

neuroscience↗

bioRxiv2021

Urocortin 3 in the posterodorsal medial amygdala mediates psychosocial stress-induced suppression of LH pulsatility in female mice

Exposure to psychosocial stress disrupts reproductive function and interferes with pulsatile luteinising hormone (LH) secretion in mammals. The posterodorsal sub-nucleus of the medial amygdala (MePD) is part of the limbic brain and is an upstream modulator of the reproductive axis as well as stress and anxiety states. Corticotropin releasing factor type-2 receptors (CRFR2) are activated in the presence of psychosocial stress together with an increased expression of the CRFR2 ligand Urocortin3 (Ucn3) in MePD of rodents. We investigate whether Ucn3 signalling in the MePD is involved in mediating the suppressive effect of psychosocial stress exposure on LH pulsatility. Firstly, we administered Ucn3 into the MePD and monitored the effect on pulsatile LH secretion in ovariectomised mice. Next, we delivered Astressin2B, a highly selective CRFR2 antagonist, intra-MePD in the presence of predator odor, 2,4,5-Trimethylthiazole (TMT) and examined the effect on LH pulses. Subsequently, we virally infected ovariectomised Ucn3-cre-tdTomato mice with inhibitory DREADDs targeting the MePD Ucn3 neurons while exposing the mice to TMT or restraint stress and examined the effect on LH pulsatility as well as corticosterone (CORT) release. Administration of Ucn3 into the MePD dose-dependently inhibited pulsatile LH secretion and intra-MePD administration of Astressin2B blocked the suppressive effect TMT on LH pulsatility. Additionally, DREADDs inhibition of MePD Ucn3 neurons blocked TMT and restraint stress-induced inhibition of LH pulses as well as CORT release in the presence of TMT. These results demonstrate for the first time that Ucn3 neurons in the MePD mediate psychosocial stress-induced suppression of the GnRH pulse generator and psychosocial stress-induced CORT secretion. Ucn3 signalling in the MePD plays a fundamental role in modulating the hypothalamic-pituitary-ganadal and hypothalamic-pituitary-adrenal axes, and this brain locus may represent a nodal centre in the crosstalk between the reproductive and stress axes.

physiology↗

bioRxiv2021

Modulation of pulsatile GnRH dynamics across the ovarian cycle: the role of excitability within the arcuate kisspeptin network

Pulsatile GnRH release is essential for normal reproductive function. Kisspeptin secreting neurons found in the arcuate nucleus, known as KNDy neurons for co-expressing neurokinin B, and dynorphin, drive pulsatile GnRH release. Furthermore, gonadal steroids regulate GnRH pulsatile dynamics across the ovarian cycle by altering KNDy neurons signalling properties. However, the precise mechanism of regulation remains mostly unknown. To better understand these mechanisms we start by perturbing the KNDy system at different stages of the estrous cycle using optogenetics. We find that optogenetic stimulation of KNDy neurons stimulates pulsatile GnRH/LH secretion in estrous mice but inhibits it in diestrous mice. These in-vivo results in combination with mathematical modelling suggest that the transition between estrus and diestrus is underpinned by well-orchestrated changes in neuropeptide signalling and in the excitability of the KNDy population controlled via glutamate signalling. Guided by model predictions, we show that blocking glutamate signalling in diestrous animals inhibits LH pulses, and that optic stimulation of the KNDy population mitigates this inhibition. In estrous mice, disruption of glutamate signalling inhibits pulses generated via sustained low-frequency optic stimulation of the KNDy population, supporting the idea that the level of network excitability is critical for pulse generation. Our results reconcile previous puzzling findings regarding the estradiol-dependent effect that several neuromodulators have on the GnRH pulse generator dynamics. Therefore, we anticipate our model to be a cornerstone for a more quantitative understanding of the pathways via which gonadal steroids regulate GnRH pulse generator dynamics. Finally, our results could inform useful repurposing of drugs targeting the glutamate system in reproductive therapy.

neuroscience↗

bioRxiv2018

Complex stopover and migratory behavior revealed using mechanistic movement models with environmentally driven dynamic parameters

AstractLong distance migration can increase lifetime fitness, but can be costly, incurring increased energetic expenses and higher mortality risks. Stopover and other en route behaviors allow animals to rest and replenish energy stores and avoid or mitigate other hazards during migration. Some animals, such as soaring birds, can subsidize the energetic costs of migration by extracting energy from flowing air. However, it is unclear how these energy sources affect or interact with behavioral processes and stopover in long-distance soaring migrants. To understand these behaviors and the effects of processes that might enhance use of flight subsidies, we developed a flexible mechanistic model to predict how flight subsidies drive migrant behavior and movement processes. The novel modelling framework incorporated time-varying parameters informed by environmental covariates to characterize a continuous range of behaviors during migration. This model framework was fit to GPS satellite telemetry data collected from a large soaring and opportunist foraging bird, the golden eagle (Aquila chrysaetos), during migration in western North America. Fitted dynamic model parameters revealed a clear circadian rhythm in eagle movement and behavior, which was directly related to thermal uplift. Behavioral budgets were complex, however, with evidence for a joint migrating/foraging behavior, resembling a slower paced fly-and-forage migration, which could facilitate efficient refueling while still ensuring migration progress. In previous work, ecological and foraging conditions are normally considered to be the key aspects of stopover location quality, but taxa that can tap energy sources from moving fluids to drive migratory locomotion, such as the golden eagle, may pace migration based on both foraging opportunities and available flight subsidies.

ecology↗