Biology subjects

Palmer, L. M.

Publications and source records attributed to Palmer, L. M..

5 recordsLinked to original sources

bioRxiv2025

Learning-induced plasticity decreases cortical engram cell dendritic excitability during memory recall

The ability to associate stimuli to create a memory is one of the most fundamental functions of the brain. Research from the past decade has revealed that memory is encoded in sparse neuronal networks active during learning called engram cells. Although the cortex is recognized as playing an important role in memory, the biophysical properties of cortical engram cells are largely unknown. To address this, we tagged engram cells in the auditory cortex during tone fear conditioning and compared their dendritic and somatic properties with neighbouring non-engram cells. Using two-photon calcium imaging, we show that tuft dendrites of engram cells had dampened, but synchronous, activity during recall. Ex vivo patch-clamp recordings illustrated that engram cells were preferentially connected with neighbouring engram cells and had decreased excitability due to a transient increase in Ih current. Together, these findings reveal Ih-driven intrinsic plasticity which leads to specific information processing in engram cells.

neuroscience↗

bioRxiv2022

LINE-1 retrotransposon activation intrinsic to interneuron development

Retrotransposons are a reservoir of cis-regulatory innovation1-3. Developmental programs that activate these elements could, in principle, manifest in lineage-specific retrotransposition. Somatic LINE-1 (L1) retrotransposon insertions have been detected in human and non-human primate neurons4-7. It is however unknown whether L1 is mobile in only some neuronal lineages, or therein regulates neurodevelopmental genes. Here, we report programmed L1 activation by SOX6, a transcription factor critical for parvalbumin (PV) interneuron development8-10. PV+ neurons permit L1 mobilization in vitro and in vivo, harbor unmethylated L1 promoters, and express full-length L1 mRNAs and proteins. Via nanopore long-read sequencing, we identify unmethylated L1 promoters proximal to PV+ neuron genes. One such L1, which promotes transcription of a novel CAPS2 gene isoform, significantly enhances neuron morphological complexity when phenotyped in vitro. These data highlight the contribution made by L1 cis-regulatory elements to PV+ neuron development and transcriptome diversity, uncovered due to L1 mobility in this milieu.

genomics↗

bioRxiv2021

Higher synaptic threshold for NMDA spike generation in human neurons

Neurons receive synaptic input primarily onto their dendrites. While we know much about the electrical properties of dendrites in rodents, we have only just started to describe their properties in the human brain. Here we investigate the capacity of human neurons to generate NMDA spikes. We find that dendritic iontophoresis of glutamate, as well as local dendritic synaptic stimulation, can evoke NMDA spikes in dendrites of human layer 2/3 pyramidal neurons. Surprisingly, however, the capacity to evoke NMDA spikes in human neurons was significantly reduced compared to that in rodent neurons. Simulations in morphologically realistic models indicated that human neurons have a higher synaptic threshold for NMDA spike generation. Using a simplified model, we show that this is primarily due to the larger diameter of human dendrites. In summary, we find reduced NMDA spike generation in human compared to rodent neurons due to the larger diameter of human dendrites.

neuroscience↗

bioRxiv2021

Cortical hyperexcitability drives dying forward ALS symptoms and pathology in mice

Amyotrophic lateral sclerosis (ALS) is a progressive fatal disorder caused by degeneration of motor neurons in the cortex and spinal cord. The origin of ALS in the central nervous system is unclear, however cortical hyperexcitability appears as an early and intrinsic feature of ALS and has been linked to degeneration of spinal motor neurons via a dying-forward mechanism. Here, we implement chemogenetics to validate the dying forward hypothesis of ALS in mice. We show that chronic hyperexcitability of corticomotoneurons induced by excitatory chemogenetics results in motor symptoms and core neuropathological hallmarks of ALS, including corticomotoneuron loss, corticospinal tract degeneration and reactive gliosis. Importantly, corticomotoneuron loss was sufficient to drive degeneration of spinal motor neurons and neuromuscular junctions (NMJs), associated with cytoplasmic TAR DNA binding protein 43 (TDP-43) pathology. These findings establish a cortical origin of ALS mediated by neuronal hyperexcitability, consistent with a dying forward mechanism of neurodegeneration.

neuroscience↗

bioRxiv2020

Higher order thalamus encodes correct goal-directed action

The thalamus is the gateway to the cortex. Cortical encoding of sensory information can therefore only be understood by considering the influence of thalamic processing on sensory input. Despite modulating sensory processing, little is known about the role of the thalamus during sensory-based behavior, let alone goal-directed behavior. Here, we use two-photon Ca2+ imaging, patch-clamp electrophysiology and optogenetics to investigate the role of axonal projections from the posteromedial nucleus of the thalamus (POm) to the forepaw area of the primary somatosensory cortex (forepaw S1) during sensory processing and goal-directed behavior. We demonstrate that POm axons are active during tactile stimulus and increase activity specifically during the response and, to a lesser extent, reward epochs of a tactile goal-directed task. Furthermore, POm axons in forepaw S1 preferentially signaled correct behavior, with greatest activity during HIT responses. This activity is important for behavioral performance, as photoinhibition of archaerhodopsin-expressing neurons in the POm decreased overall behavioral success. Direct juxtacelluar recordings in the awake state illustrates POm neurons fire sustained action potentials during tactile stimulus. This tactile-evoked POm firing pattern was used during ChR2 photoactivation of POm axons in forepaw S1, revealing that action potentials in layer 2/3 (L2/3) pyramidal neurons are inhibited during sustained POm input. Taken together, POm axonal projections in forepaw S1 encode correct goal-directed active behavior, leading to GABAA-mediated inhibition of L2/3 pyramidal neurons.

neuroscience↗