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BioRxiv : the Preprint Server For... Jun 2024Traumatic social experiences redefine socially motivated behaviors to enhance safety and survival. Although many brain regions have been implicated in signaling a social...
Traumatic social experiences redefine socially motivated behaviors to enhance safety and survival. Although many brain regions have been implicated in signaling a social threat, the mechanisms by which global neural networks regulate such motivated behaviors remain unclear. To address this issue, we first combined traditional and modern behavioral tracking techniques in mice to assess both approach and avoidance, as well as sub-second behavioral changes, during a social threat learning task. We were able to identify previously undescribed body and tail movements during social threat learning and recognition that demonstrate unique alterations into the behavioral structure of social motivation. We then utilized inter-regional correlation analysis of brain activity after a mouse recognizes a social threat to explore functional communication amongst brain regions implicated in social motivation. Broad brain activity changes were observed within the nucleus accumbens, the paraventricular thalamus, the ventromedial hypothalamus, and the nucleus of reuniens. Inter-regional correlation analysis revealed a reshaping of the functional connectivity across the brain when mice recognize a social threat. Altogether, these findings suggest that reshaping of functional brain connectivity may be necessary to alter the behavioral structure of social motivation when a social threat is encountered.
PubMed: 38948883
DOI: 10.1101/2024.06.17.599379 -
BioRxiv : the Preprint Server For... Jun 2024Genomic diversity in a pathogen population is the foundation for evolution and adaptations in virulence, drug resistance, pathogenesis, and immune evasion....
UNLABELLED
Genomic diversity in a pathogen population is the foundation for evolution and adaptations in virulence, drug resistance, pathogenesis, and immune evasion. Characterizing, analyzing, and understanding population-level diversity is also essential for epidemiological and forensic tracking of sources and revealing detailed pathways of transmission and spread. For bacteria, culturing, isolating, and sequencing the large number of individual colonies required to adequately sample diversity can be prohibitively time-consuming and expensive. While sequencing directly from a mixed population will show variants among reads, they cannot be linked to reveal allele combinations associated with particular traits or phylogenetic inheritance patterns. Here, we describe the theory and method of how population sequencing directly from a mixed sample can be used in conjunction with sequencing a very small number of colonies to describe the phylogenetic diversity of a population without haplotype reconstruction. To demonstrate the utility of population sequencing in capturing phylogenetic diversity, we compared isogenic clones to population sequences of from the sputum of a single patient. We also analyzed population sequences of derived from different people and different body sites. Sequencing results confirm our ability to capture and characterize phylogenetic diversity in our samples. Our analyses of populations led to the surprising discovery that the pathogen population is highly structured in sputum, suggesting that for some pathogens, sputum sampling may preserve structuring in the lungs and thus present a non-invasive alternative to understanding colonization, movement, and pathogen/host interactions. Our analyses of samples show how comparing phylogenetic diversity across populations can reveal directionality of transmission between hosts and across body sites, demonstrating the power and utility for characterizing the spread of disease and identification of reservoirs at the finest levels. We anticipate that population sequencing and analysis can be broadly applied to accelerate research in a broad range of fields reliant on a foundational understanding of population diversity.
AUTHOR SUMMARY
The ability to characterize diversity in a single bacterial population (i.e., a single host or even a single body site) is critical for understanding adaptation and evolution, with far-reaching implications on disease treatment and prevention that include revealing patterns of spread and persistence. While the scientific community has made great strides in sequencing methods to characterize single colonies and entire communities, there is a dearth of studies at the population level. This is because 1) the need to culture and sequence a sufficiently representative number of isogenic colonies is prohibitive, and 2) the theoretical foundation for characterizing a population by sequencing a single sample (as is done for microbiome and metagenomic analyses) has not been developed. Here, we introduce this theoretical foundation and validate its applicability by characterizing a lung infection caused by . We also demonstrate the utility of this method in determining the directionality of spread of between people and across body sites within the same host (a level of spatial resolution that has not been previously performed). We anticipate that this work will open the door to a host of new studies and discoveries across a diverse set of microbiological fields.
PubMed: 38948873
DOI: 10.1101/2024.06.18.599478 -
BioRxiv : the Preprint Server For... Jun 2024Matching arousal level to the motor activity of an animal is important for efficiently allocating cognitive resources and metabolic supply in response to behavioral...
Matching arousal level to the motor activity of an animal is important for efficiently allocating cognitive resources and metabolic supply in response to behavioral demands, but how the brain coordinates changes in arousal and wakefulness in response to motor activity remains an unclear phenomenon. We hypothesized that the locus coeruleus (LC), as the primary source of cortical norepinephrine (NE) and promoter of cortical and sympathetic arousal, is well-positioned to mediate movement-arousal coupling. Here, using a combination of physiological recordings, fiber photometry, optogenetics, and behavioral tracking, we show that the LC activation is tightly coupled to the return of organized movements during waking from an anesthetized state. Moreover, in an awake animal, movement initiations are coupled to LC activation, while movement arrests, to LC deactivation. We also report that LC activity covaries with the depth of anesthesia and that LC photoactivation leads to sympathetic activation, consistent with its role in mediating increased arousal. Together, these studies reveal a more nuanced, modulatory role that LC plays in coordinating movement and arousal.
PubMed: 38948871
DOI: 10.1101/2024.06.18.599619 -
BioRxiv : the Preprint Server For... Jun 2024Understanding how animals coordinate movements to achieve goals is a fundamental pursuit in neuroscience. Here we explore how neurons that reside in posterior...
Understanding how animals coordinate movements to achieve goals is a fundamental pursuit in neuroscience. Here we explore how neurons that reside in posterior lower-order regions of a locomotor system project to anterior higher-order regions to influence steering and navigation. We characterized the anatomy and functional role of a population of ascending interneurons in the ventral nerve cord of larvae. Through electron microscopy reconstructions and light microscopy, we determined that the cholinergic 19f cells receive input primarily from premotor interneurons and synapse upon a diverse array of postsynaptic targets within the anterior segments including other 19f cells. Calcium imaging of 19f activity in isolated central nervous system (CNS) preparations in relation to motor neurons revealed that 19f neurons are recruited into most larval motor programmes. 19f activity lags behind motor neuron activity and as a population, the cells encode spatio-temporal patterns of locomotor activity in the larval CNS. Optogenetic manipulations of 19f cell activity in isolated CNS preparations revealed that they coordinate the activity of central pattern generators underlying exploratory headsweeps and forward locomotion in a context and location specific manner. In behaving animals, activating 19f cells suppressed exploratory headsweeps and slowed forward locomotion, while inhibition of 19f activity potentiated headsweeps, slowing forward movement. Inhibiting activity in 19f cells ultimately affected the ability of larvae to remain in the vicinity of an odor source during an olfactory navigation task. Overall, our findings provide insights into how ascending interneurons monitor motor activity and shape interactions amongst rhythm generators underlying complex navigational tasks.
PubMed: 38948859
DOI: 10.1101/2024.06.17.598162 -
BioRxiv : the Preprint Server For... Jun 2024Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of...
Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex.
Decreased excitability of pyramidal tract neurons in layer 5B (PT5B) of primary motor cortex (M1) has recently been shown in a dopamine-depleted mouse model of parkinsonism. We hypothesized that decreased PT5B neuron excitability would substantially disrupt oscillatory and non-oscillatory firing patterns of neurons in layer 5 (L5) of primary motor cortex (M1). To test this hypothesis, we performed computer simulations using a previously validated computer model of mouse M1. Inclusion of the experimentally identified parkinsonism-associated decrease of PT5B excitability into our computational model produced a paradoxical increase in rest-state PT5B firing rate, as well as an increase in beta-band oscillatory power in local field potential (LFP). In the movement-state, PT5B population firing and LFP showed reduced beta and increased high-beta, low-gamma activity of 20-35 Hz in the parkinsonian, but not in control condition. The appearance of beta-band oscillations in parkinsonism would be expected to disrupt normal M1 motor output and contribute to motor activity deficits seen in patients with Parkinson's disease (PD).
PubMed: 38948850
DOI: 10.1101/2024.05.23.595566 -
BioRxiv : the Preprint Server For... Jun 2024Anaphase is tightly controlled in space and time to ensure proper separation of chromosomes. The mitotic spindle, the self-organized microtubule structure driving...
Anaphase is tightly controlled in space and time to ensure proper separation of chromosomes. The mitotic spindle, the self-organized microtubule structure driving chromosome segregation, scales in size with the available cytoplasm. Yet, the relationship between spindle size and chromosome movement remains poorly understood. Here, we address how the movement of chromosomes changes during the cleavage divisions of the blastoderm. We show that the speed of chromosome separation gradually decreases during the 4 nuclear divisions of the blastoderm. This reduction in speed is accompanied by a similar reduction in the length of the spindle, thus ensuring that these two quantities are tightly linked. Using a combination of genetic and quantitative imaging approaches, we find that two processes contribute to controlling the speed at which chromosomes move at mitotic exit: the activity of molecular motors important for microtubule depolymerization and the cell cycle oscillator. Specifically, we found that the levels of Klp10A, Klp67A, and Klp59C, three kinesin-like proteins important for microtubule depolymerization, contribute to setting the speed of chromosome separation. This observation is supported by quantification of microtubule dynamics indicating that poleward flux rate scales with the length of the spindle. Perturbations of the cell cycle oscillator using heterozygous mutants of mitotic kinases and phosphatases revealed that the duration of anaphase increases during the blastoderm cycles and is the major regulator of chromosome velocity. Thus, our work suggests a potential link between the biochemical rate of mitotic exit and the forces exerted by the spindle. Collectively, we propose that the cell cycle oscillator and spindle length set the speed of chromosome separation in anaphase.
PubMed: 38948726
DOI: 10.1101/2024.06.17.598879 -
BioRxiv : the Preprint Server For... Jun 2024Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion,...
Flagella are highly complex rotary molecular machines that enable bacteria to not only migrate to optimal environments but to also promote range expansion, competitiveness, virulence, and antibiotic survival. Flagellar motility is an energy-demanding process, where the sum of its production (biosynthesis) and operation (rotation) costs has been estimated to total ∼10% of the entire energy budget of an cell. The acquisition of such a costly adaptation process is expected to secure short-term benefits by increasing competitiveness and survival, as well as long-term evolutionary fitness gains. While the role of flagellar motility in bacterial survival has been widely reported, its direct influence on the rate of evolution remains unclear. We show here that both production and operation costs contribute to elevated mutation frequencies. Our findings suggest that flagellar movement may be an important player in tuning the rate of bacterial evolution.
PubMed: 38948722
DOI: 10.1101/2024.06.21.600093 -
BioRxiv : the Preprint Server For... Jun 2024Hairpin forming expanded CAG/CTG repeats pose significant challenges to DNA replication which can lead to replication fork collapse. Long CAG/CTG repeat tracts relocate...
UNLABELLED
Hairpin forming expanded CAG/CTG repeats pose significant challenges to DNA replication which can lead to replication fork collapse. Long CAG/CTG repeat tracts relocate to the nuclear pore complex to maintain their integrity. Forks impeded by DNA structures are known to activate the DNA damage checkpoint, thus we asked whether checkpoint proteins play a role in relocation of collapsed forks to the nuclear periphery in . We show that relocation of a (CAG/CTG) tract is dependent on activation of the Mrc1/Rad53 replication checkpoint. Further, checkpoint-mediated phosphorylation of the kinetochore protein Cep3 is required for relocation, implicating detachment of the centromere from the spindle pole body. Activation of this pathway leads to DNA damage-induced microtubule recruitment to the repeat. These data suggest a role for the DNA replication checkpoint in facilitating movement of collapsed replication forks to the nuclear periphery by centromere release and microtubule-directed motion.
HIGHLIGHTS
The DNA damage checkpoint is needed for relocation of a structure-forming CAG repeat tract to the nuclear pore complexThe importance of Mrc1 (hClaspin) implicates fork uncoupling as the initial checkpoint signalPhosphorylation of the Cep3 kinetochore protein by Dun1 kinase modulates centromere release, which is critical for collapsed fork repositioningDamage-inducible nuclear microtubules colocalize with the CAG repeat locus and are required for relocalizationEstablishes a new role for the DNA replication and DNA damage checkpoint response to trigger repositioning of collapsed forks within the nucleus.
PubMed: 38948692
DOI: 10.1101/2024.06.17.599319 -
Postepy Psychiatrii Neurologii Mar 2024Tolosa-Hunt syndrome (THS) is a rare cause of painful ophtalmoplegia with different clinical manifestations. It is described as a unilateral periorbital headache with...
PURPOSE
Tolosa-Hunt syndrome (THS) is a rare cause of painful ophtalmoplegia with different clinical manifestations. It is described as a unilateral periorbital headache with concomitant dysfunction of at least one out of the IIIrd, IVth and VIth cranial nerves due to the granulomatous inflammation of periorbital structures, but no underlying cause has been established.
CASE DESCRIPTION
We present six patients referred to the Neurology Department due to a unilateral headache with ipsilateral paresis of at least one cranial nerve responsible for eye movements. The THS diagnostic criteria of the International Headache Disorders Classification (ICHD-3) were applied and analysed. Few patients had atypical clinical manifestations according to these criteria.
COMMENT
Diagnosing THS may prove very challenging. There is a lack of specific markers for the disorder, whereas diagnostic criteria leave a wide area for misdiagnosis. The diagnostic approach should be focused on the exclusion of other pathologies because typical steroid therapy may prove fatal in otherwise benign cases.
PubMed: 38948688
DOI: 10.5114/ppn.2023.135176 -
Turkish Journal of Physical Medicine... Jun 2024This study aimed to objectively and quantitatively exhibit morning stiffness by using electrophysiological methods.
OBJECTIVES
This study aimed to objectively and quantitatively exhibit morning stiffness by using electrophysiological methods.
PATIENTS AND METHODS
The prospective, controlled study was conducted with 52 participants between February 2013 and February 2014. Of the participants, 26 were recruited among RA patients (3 males, 23 females; mean age: 55.9±11.2 years; range, 24 to 74 years) followed at the rheumatology clinic, and 26 were healthy subjects (4 males, 22 females; mean age: 54.9±8.3 years; range, 41 to 70 years) for the control group. Duration and severity of morning stiffness were recorded for all participants. Activity of disease and functional status were evaluated by the Disease Activity Score 28 and Health Assessment Questionnaire (HAQ), respectively. Electrophysiological reaction times, severity of pain (Visual Analog Scale), HAQ, and grip strength were measured for each participant twice in 24 h in the morning (08:00-09:00 am) and afternoon (03:00-05:00 pm).
RESULTS
In the RA group, motor reaction and response times and severity of pain values were significantly lower in the afternoon compared to the morning (p=0.030, p=0.031, and p=0.002, respectively), and hand grip strengths were significantly higher in the afternoon (p=0.007). In the control group, no change was observed between morning and afternoon measurements in the strength and reaction time variables.
CONCLUSION
Our hypothesis that stiffness would slow down the movements in the morning in RA was supported by the prolonged motor and response times in the morning compared to the afternoon. However, in the control group (no morning stiffness), there was no difference in reaction time variables between the morning and afternoon, objectively demonstrating the concept of morning stiffness in this study.
PubMed: 38948637
DOI: 10.5606/tftrd.2024.12219