Biology subjects

Downer, J.

Publications and source records attributed to Downer, J..

3 recordsLinked to original sources

bioRxiv2026

Large-scale cerebrospinal fluid proteomics identifies diagnostic biomarker candidates across the clinico-pathological continuum of frontotemporal lobar degeneration

Frontotemporal lobar degeneration (FTLD), predominantly comprised of tau and TDP-43 proteinopathies, is a common cause of early-onset dementia. Biomarkers that reliably classify FTLD subtypes are limited, thereby hindering in-vivo diagnosis and clinical trial stratification. We conducted large-scale, multi-platform cerebrospinal fluid proteomics in 566 individuals, including 274 FTLD-spectrum (48 autopsy-confirmed FTLD-TDP, 90 autopsy-confirmed FTLD-tau), 171 Alzheimers disease, and 95 controls. In neuropathological subtype contrasts, elevated matrix metalloproteinase MMP10 classified Picks disease (PiD) versus other subtypes with near-perfect accuracy across proteomic platforms. We further validated CSF MMP10 as a potential PiD diagnostic biomarker via a targeted immunoassay in an independent, autopsy-confirmed FTLD cohort. Post-synaptic proteins HOMER1 and DLG4 exhibited elevations across FTLD-TDP subtypes (A, B, and C) versus FTLD-tau. Network analysis identified RNA metabolism and pro-inflammatory signatures in FTLD-TDP, and cytoskeletal and heat shock signatures in progressive supranuclear palsy. These findings reveal candidate diagnostic biomarkers and proteomic pathways underlying FTLD clinico-pathological heterogeneity.

neuroscience↗

bioRxiv2024

MICROENDOSCOPIC CALCIUM IMAGING IN SUPPLEMENTARY MOTOR AREA AND PRIMARY MOTOR CORTEX OF RHESUS MACAQUES AT REST AND DURING ARM MOVEMENT

The study of motor cortices in non-human primates is relevant to our understanding of human motor control, both in healthy conditions and in movement disorders. Calcium imaging and miniature microscopes allow the study of multiple genetically identified neurons with excellent spatial resolution. We used this method to examine activity patterns of projection neurons in deep layers of the supplementary motor (SMA) and primary motor areas (M1) in four rhesus macaques. We implanted gradient index lenses and expressed GCaMP6f to image calcium transients while the animals were at rest or engaged in an arm reaching task. We tracked the activity of SMA and M1 neurons across conditions, examined cell pairs for synchronous activity, and assessed whether SMA and M1 neuronal activation followed specific sequential activation patterns. We demonstrate the value of in vivo calcium imaging for studying patterns of activity in groups of corticofugal neurons in SMA and M1. HIGHLIGHTSO_LIUse of one-photon miniature microscopes and microendoscopic calcium imaging to study the activity of cortical projection neurons in the supplementary motor area (SMA) and primary motor cortex (M1) of rhesus macaques at rest or performing simple arm reaches. C_LIO_LICalcium transients were related to arm reaches and showed directional sensitivity in a proportion of cells in SMA and M1. C_LIO_LISubsets of cell pairs showed coactivation in SMA and M1 during rest and reaching tasks. The strength of coactivity was not related to the distance between cells. C_LIO_LISMA and M1 neurons displayed sequential activation patterns. C_LIO_LIWe demonstrated that microendoscopic calcium imaging can be used to assess dynamic activity within genetically identified cell populations in deep layers of SMA and M1. C_LI

neuroscience↗

bioRxiv2020

Hierarchical effects of choice related activity and neural encoding during feature selective attention

Selective attention is necessary to sift through, form a coherent percept of, and make behavioral decisions on the vast amount of information present in most sensory environments. How and where selective attention is employed in cortex and how this perceptual information then informs the relevant behavioral decisions is still not well understood. Studies probing selective attention and decision making in visual cortex have been enlightening as to how sensory attention might work in that modality; whether or not similar mechanisms are employed in auditory attention is not yet clear. Therefore, we trained rhesus macaques on a feature selective attention task, where they switched between reporting changes in temporal (amplitude modulation, AM) and spectral (carrier bandwidth) features of a broadband noise stimulus. We investigated how the encoding of these features by single neurons in primary (A1) and secondary (lateral belt, ML) auditory cortex were affected by the different attention conditions. We found that neurons in A1 and ML showed mixed-selectivity to the sound and task features. We found no difference in AM encoding between the attention conditions. We found that choice-related activity in both A1 and ML neurons shifts between attentional conditions. This finding suggests that choice-related activity in auditory cortex does not simply reflect motor preparation or action, and supports the relationship between reported choice-related activity and the decision and perceptual process. New & NoteworthyWe recorded from primary and secondary auditory cortex while monkeys performed a non-spatial feature attention task. Both areas exhibited rate-based choice-related activity. The manifestation of choice-related activity was attention-dependent, suggesting that choice-related activity in auditory cortex does not simply reflect arousal or motor influences, but relates to the specific perceptual choice. The lack of temporal-based choice activity is consistent with growing evidence that subcortical, but not cortical, single neurons inform decisions through temporal envelope following.

neuroscience↗