bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, June 27th, 2024
| Time |
Event |
| 1:50a |
Anhedonic behaviour in a TLR7-driven neuroinflammation mouse model is associated with impaired thalamostriatal signalling and immune cell ingress into the brain
Depression is a heterogenous condition driven by multiple aetiologies, which make its pathophysiology challenging to map. Stratifying depression by underlying biological causes may allow for more effective, targeted treatments. Immune-mediated inflammation is present in around 20% of individuals with depression and provides a potential mechanistic pathway for some key symptoms such as reward / hedonic impairment. Here we used a non-invasive model of neuroinflammation, topical application of Aldara (a TLR7/8 agonist) for 3 days in mice, to explore relationships between the intracerebral immune response, neural circuitry and behaviours closely linked to depression: motivation, reward and anxiety.
Mice that were treated with Aldara exhibited anhedonia-like behaviour and impairments in intrinsic motivational behaviours (measured through assays such as sucrose preference and nest-building tests) relative to untreated controls, but displayed little anxiety-like behaviour. Aldara-driven neuroinflammation was associated with evidence of immune cell (including lymphoid and myeloid cells) ingression into the brain, and both microglia and astrocytes showed evidence of activation. Within 4 to 6 hours of Aldara treatment, neurons in midline thalamus showed strongly increased Fos immunoreactivity relative to controls. Optogenetic activation of midline thalamic projections onto ventral striatum medium spiny neurons (MSNs) revealed that Aldara treatment substantially reduced the magnitude of the evoked thalamic AMPA receptor-mediated EPSC, but with no change to the AMPA/NMDA ratio nor change in the frequency of amplitude of spontaneous EPSP. Finally, whole brain transcriptome overrepresentation analysis revealed that Aldara treatment led to significant upregulation of genes associated with immune response and downregulation of genes associated with glutamate metabolism and synaptic transmission.
Altogether, our data suggest potential, testable mechanisms through which neuroinflammation can drive anhedonic-like behaviour through activation of resident neural cells, infiltrating activated immune cells and functional changes in thalamostriatal circuitry consistent with increased extrasynaptic glutamate. | | 5:45a |
Evolution of iGluR ligand specificity, polyamine regulation, and ion selectivity inferred from a placozoan Epsilon receptor
Epsilon ionotropic glutamate receptors (iGluRs) belong to a recently described sub-family of metazoan receptors that is distinct from the AMPA, Kainate, Delta, and Phi (i.e., AKDF) sub-family, the NMDA sub-family, and the Lambda subfamily. Here, we sought to better understand the evolutionary and functional properties of Epsilon receptors by focusing on homologues from the basal invertebrate Trichoplax adhaerens (phylum Placozoa). We provide an updated species-guided phylogeny of eukaryotic iGluRs, and a comprehensive phylogeny of placozoan receptors uncovering marked diversification of Epsilon receptors within three conserved subclades, and four invariable subclades of AKDF receptors. Detailed functional characterization of the T. adhaerens Epsilon receptor GluE1A revealed robust activation by glycine, alanine, serine, and valine, but not glutamate. Through combined of structural modeling and mutation experiments, we used GluE1A to test the hypothesis that only a small set of amino acids in the ligand binding domain determine ligand selectivity. Mutation of just three amino acids converted GluE1A selectivity to glutamate, resulted in nascent sensitivity to AMPA, and increased sensitivity to the AMPA/Kainate receptor blocker CNQX. Lastly, combined modeling and mutation experiments revealed that an atypical serine residue in the pore NQR site of GluE1A, along with an aspartate four amino acids downstream, confers sensitivity to voltage-dependent polyamine block, while the serine alone diminishes both polyamine block and Ca2+ permeation compared to asparagine and glutamine residues of AMPA and Kainate receptors. Altogether, we demonstrate conserved molecular determinants for polyamine regulation between Epsilon and AKDF receptors, and evidence that natural variations in NQR residues have important implications for ion permeation and regulation by polyamines. | | 8:39a |
Midline Assembloids Reveal Regulators of Human Axon Guidance
Organizers are specialized cell populations that orchestrate cell patterning and axon guidance in the developing nervous system. Although non-human models have led to fundamental discoveries about the organization of the nervous system midline by the floor plate, an experimental model of human floor plate would enable broader insights into regulation of human neurodevelopment and midline connectivity. Here, we have developed stem cell-derived organoids resembling human floor plate (hFpO) and assembled them with spinal cord organoids (hSpO) to generate midline assembloids (hMA). We demonstrate that hFpO promote Sonic hedgehog-dependent ventral patterning of human spinal progenitors and Netrin-dependent guidance of human commissural axons, paralleling non-human models. To investigate evolutionary-divergent midline regulators, we profiled the hFpO secretome and identified 27 evolutionarily divergent genes between human and mouse. Utilizing the hMA platform, we targeted these candidates in an arrayed CRISPR knockout screen and reveal that GALNT2, a gene involved in O-linked glycosylation, impairs floor plate-mediated guidance of commissural axons in humans. This novel platform extends prior axon guidance discoveries into human-specific neurobiology with implications for mechanisms of nervous system evolution and neurodevelopmental disorders. | | 8:39a |
Purkinje Cell-specific Deficiency in SEL1L-HRD1 Endoplasmic Reticulum-Associated Degradation Causes Progressive Cerebellar Ataxia in Mice
Recent studies have identified multiple genetic variants of SEL1L-HRD1 ER-associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here we show that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell-specific deletion of SEL1L (Sel1LPcp2Cre) exhibit motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy (TEM) analysis reveals dilated ER and fragmented nuclei in Purkinje cells of adult Sel1LPcp2Cre mice, indicative of altered ER homeostasis and cell death. Lastly, loss of Purkinje cells is associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellum of Sel1LPcp2Cre mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.
One-sentence summarySEL1L-HRD1 ERAD is indispensable for Purkinje cell function and cerebellar ataxia pathogenesis in mice. | | 8:39a |
Left-Right Brain-Wide Asymmetry of Neuroanatomy in the Mouse Brain
Left-right asymmetry of the human brain is widespread through its anatomy and function. However, limited microscopic understanding of it exists, particularly for anatomical asymmetry where there are few well-established animal models. In humans, most of the brain shows subtle, population-average, regional asymmetries in cortical thickness or surface area. In addition, a macro-scale twisting called the cerebral petalia exists in which the right hemisphere protrudes anteriorly relative to the left. Here, we ask whether neuroanatomical asymmetries can be observed in mice, leveraging 6 different neuroimaging cohorts of animals from 5 different research groups ([~]3,500 animals in total). We found an anterior-posterior pattern of volume asymmetry in mice, where anterior regions are larger on the right while posterior regions are larger on the left. This pattern appears driven by a similar trend in surface area asymmetry and is supported by a concordant pattern of positional asymmetries. The cerebral hemisphere as a whole appears shifted anteriorly on the right while the brainstem and cerebellum appear shifted anteriorly on the left. These results together indicate a small torsion of the brain is present in mice, similar to the cerebral petalia in humans. By establishing a signature of anatomical brain asymmetry in mice, we aim to provide a foundation for future studies to probe the mechanistic underpinnings of anatomical brain asymmetry seen in humans - a feature of the brain with extremely limited understanding. | | 1:35p |
Amygdala-predominant α-synuclein pathology exacerbates hippocampal neuron loss in Alzheimer's disease
Misfolded -synuclein (Syn) protein accumulates in 43-63% of individuals with symptomatic Alzheimers disease (AD). Two main patterns of co-morbid Syn pathology have been identified: caudo-rostral and amygdala-predominant, with the latter being more common in AD. Syn pathology has been shown to interact with DNA-binding protein 43 (TDP-43) and abnormally phosphorylated Tau protein (pTau). These proteins tend to accumulate in the amygdala, yet the specific role of amygdala-predominant Syn pathology in the progression of AD and hippocampal degeneration remains unclear.
In this cross-sectional study, we analyzed 291 autopsy brains from both demented and non-demented elderly individuals neuropathologically. Neuronal density in the CA1 region of the hippocampus was assessed using hematoxylin-stained sections for all cases. We semi-quantitatively evaluated Syn pathology severity in six brain regions and stratified the cases into the two spreading patterns. In 99 AD cases, we assessed limbic-predominant age-related TDP-43 neuropathological changes (LATE-NC), CA1 pTau density, and cerebral amyloid angiopathy (CAA). Structural equation modeling analysis was conducted based on the assessed pathological parameters in AD patients.
We identified an association between the amygdala-predominant Syn pathology pattern and decreased neuronal density in the CA1 region. AD patients with an amygdala-predominant Syn pattern exhibited the most severe pTDP-43 pathology among all groups, while those with the caudo-rostral pattern had the lowest severity of AD-related pathological changes including CAA type 1. Our model revealed that the relationship between Syn pathology and CA1 neuron loss is mediated through pTau and LATE-NC.
Our results indicate that amygdala-predominant Syn pathology, in contrast to Syn pathology with a caudo-rostral pattern, significantly contributes to hippocampal neuron loss, potentially by accelerating TDP-43 and pTau pathologies. This finding, along with observed neuropathological differences between AD patients with these two Syn spreading patterns, underscores the need for precise stratification of patients. The stratification should consider not only the molecular and morphological identity of co-pathologies but also the distribution pattern of the respective co-pathologies. | | 2:54p |
Confirmation Bias through Selective Use of Evidence in Human Cortex
Decision-makers often process new evidence selectively, depending on their current beliefs about the world. We asked whether such confirmation biases result from biases in the encoding of sensory evidence in the brain, or alternatively in the utilization of encoded evidence for behavior. Human participants estimated the source of a sequence of visual-spatial evidence samples while we measured cortical population activity with magnetoencephalography (MEG). Halfway through the sequence, participants were prompted to judge the more likely source category. Their processing of subsequent evidence depended on its consistency with the previously chosen category, but the encoding of evidence in cortical activity did not. Instead, the encoded evidence in parietal and primary visual cortex contributed less to the estimation report when that evidence was inconsistent with the previous choice. We conclude that confirmation bias originates from the way in which decision-makers utilize information encoded in the brain. This provides room for deliberative control. | | 2:54p |
Selective suppression of oligodendrocyte-derived amyloid beta rescues neuronal dysfunction in Alzheimer's Disease
Reduction of amyloid beta (Abeta) has been shown to be effective in treating Alzheimer's Disease (AD), but the underlying assumption that neurons are the main source of pathogenic Abeta; is untested. Here we challenge this prevailing belief by demonstrating that oligodendrocytes are an important source of Abeta, and play a key role in promoting abnormal neuronal hyperactivity in AD. We show that selectively suppressing oligodendrocyte Abeta production improves AD brain pathology and restores neuronal function in vivo. Our findings suggest that targeting oligodendrocyte Abeta production could be a promising therapeutic strategy for treating AD. | | 3:20p |
Pregnancy History and Estradiol Influence Spatial Memory, Hippocampal Plasticity, and Inflammation in Middle-aged Rats
Pregnancy and motherhood (parity) can have long-term effects on cognition and brain aging in both humans and rodents. Estrogens are related to cognitive function and neuroplasticity. Estrogens can improve cognition in postmenopausal women, but the evidence is mixed, in part due to differences in hormone therapy dose and composition. In addition, past pregnancy influences brain aging and cognition, with earlier age of first pregnancy being associated with poorer outcomes with aging. However, few studies have examined specific features of pregnancy history such as the age of first pregnancy or the possible mechanisms underlying these changes. We examined whether maternal age at first pregnancy and estradiol treatment differentially affected hippocampal neuroplasticity, inflammation, activation, and cognition in middle-age. Thirteen-month-old rats (who were nulliparous (never mothered) or previously primiparous (had a litter) at 3 months or 7 months) received daily injections of estradiol (or sesame oil vehicle) for sixteen days and were tested on the Morris Water Maze. An older age of first pregnancy was associated with impaired spatial memory but improved performance on reversal training, and increased new neurons in the ventral hippocampus compared to the other groups. Estradiol decreased total activation and percent activation of new neurons in the dorsal hippocampus, regardless of parity history. Estradiol also decreased the production of anti-inflammatory cytokines based on age of first pregnancy. This work suggests that estradiol affects neuroplasticity and neuroinflammation in middle age, and that pregnancy history can have long lasting effects on hippocampus structure and function. | | 4:30p |
Post-retrieval noradrenergic activation impairs subsequent memory depending on cortico-hippocampal reactivation
When retrieved, seemingly stable memories can become sensitive to modification through significant events, such as acute stress. While memory dynamics after retrieval have profound implications, for instance, in eyewitness testimony or aberrant memory in mental disorders, the mechanisms underlying these dynamics remain poorly understood. Here, we show in healthy humans that increases in noradrenaline after memory retrieval impairs subsequent remembering, depending on hippocampal and cortical reactivation during retrieval. In a three-day fMRI study, we measured brain activity during initial encoding (Day 1), 24h-delayed memory cueing accompanied by administration of placebo, hydrocortisone, or the 2-adrenoceptor antagonist yohimbine (Day 2), and final recall, 24h later (Day 3). While post-retrieval hydrocortisone did not affect subsequent memory (i.e., final recall), the impairing effect of yohimbine on final recall depended on the strength of hippocampal reactivation and category-level reinstatement in ventral temporal cortex during Day 2 retrieval. Notably, the effect of yohimbine on subsequent memory was contingent specifically on the neural reactivation during retrieval. While patterns from online reactivation were also reinstated in the post-retrieval rest-period, this offline reinstatement did not interact with the pharmacological manipulation. Additionally, the original memory trace from encoding was not significantly reactivated during retrieval and not reinstated offline during rest, further supporting the critical dependency of post-retrieval manipulations on the neural signal emerging during retrieval-related reactivation. Our findings demonstrate that, depending on the neural reactivation of memories, noradrenergic arousal after retrieval can alter the future accessibility of consolidated memories. | | 11:46p |
Causal Cortical and Thalamic Connections in the Human Brain
The brain's functional architecture is intricately shaped by causal connections between its cortical and subcortical structures. Here, we studied 27 participants with 4864 electrodes implanted across the anterior, mediodorsal, and pulvinar thalamic regions, and the cortex. Using data from electrical stimulation procedures and a data-driven approach informed by neurophysiological standards, we dissociated three unique spectral patterns generated by the perturbation of a given brain area. Among these, a novel waveform emerged, marked by delayed-onset slow oscillations in both ipsilateral and contralateral cortices following thalamic stimulations, suggesting a mechanism by which a thalamic site can influence bilateral cortical activity. Moreover, cortical stimulations evoked earlier signals in the thalamus than in other connected cortical areas suggesting that the thalamus receives a copy of signals before they are exchanged across the cortex. Our causal connectivity data can be used to inform biologically-inspired computational models of the functional architecture of the brain. |
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