Biology subjects

Dietrich, M. O.

Publications and source records attributed to Dietrich, M. O..

11 recordsLinked to original sources

bioRxiv2026

Cholera toxin remodels intestinal immunity and suppresses systemic metabolism

Cholera toxin (CTx) is a potent enterotoxin and widely used mucosal adjuvant, yet the acute host response to CTx itself, in the absence of a co-administered antigen, remains vague. In this study, we integrated physiological and metabolic phenotyping with intestinal transcriptomics, epithelial imaging, immune profiling, hepatic gene-expression analysis, and paired microbiome profiling to characterize the response to a single oral CTx exposure in mice. Within 24 h, CTx remodeled immune-cell composition in both epithelial and lamina propria compartments, with responses shaped by sex and genetic background. Recurrent changes included increased epithelial group 3 innate lymphoid cells, reduced lamina propria ROR{gamma}t+ regulatory T cells, and decreased epithelial ILC1/NK cells in males of both strains. CTx also increased villus DCLK1+ tuft cells and reduced MUC2 immunoreactivity. Jejunal transcriptomics revealed induction of inflammatory defense, glycolytic, autophagy, and lipid-utilization programs together with suppression of proliferative and mitochondrial programs, consistent with coordinated stress adaptation. These local changes were accompanied by rapid restructuring of the fecal microbial community and by systemic hypometabolism, despite markedly different hypothermic responses across strains. CTx also elicited a selective hepatic stress and metabolic program, including conserved suppression of Cyp7a1 across sexes and strains. Together, these findings show that CTx alone rapidly reorganizes the intestinal immune, epithelial, metabolic, and microbial environment while suppressing whole-body metabolism. This work provides an integrated framework for understanding the acute host response to CTx and for interpreting its widespread use as a mucosal adjuvant.

immunology↗

bioRxiv2026

A hypothalamic circuit links hunger to mesolimbic dopamine to drive feeding

Hunger enhances the motivational value of food, but the neural circuits linking homeostatic hunger neurons to dopamine systems remain poorly understood. Here, we identify a hypothalamic-midbrain neural circuit through which AgRP neurons engage the mesolimbic dopamine system. We demonstrate that AgRP neuron activity is both necessary and sufficient for the potentiated dopamine response to food by hunger, and that they achieve this by reducing inhibitory drive onto midbrain dopamine neurons. Importantly, this AgRP neuron-evoked dopamine signaling is required for subsequent food intake. Mechanistically, we find that AgRP neuron projections to NPY-sensitive paraventricular hypothalamic neurons selectively amplify food-evoked dopamine release to promote feeding behavior. These findings reveal a circuit mechanism through which hunger recruits dopamine signaling to transform physiological need into motivated feeding behavior.

neuroscience↗

bioRxiv2025

Erratic Maternal Care Induces Avoidant-Like Attachment Deficits in a Mouse Model of Early Life Adversity

Attachment theory offers an important clinical framework for understanding and treating negative effects of early life adversity. Attachment styles emerge during critical periods of development in response to caregivers ability to consistently meet their offsprings needs. Attachment styles are classified as secure or insecure (anxious, avoidant, or disorganized), with rates of insecure attachment rising in high-risk populations and correlating with a plethora of negative health outcomes throughout life. Despite its importance, little is known about the neural basis of attachment. Work in rats has demonstrated that limited bedding and nesting (LB) impairs maternal care and produces abnormal maternal attachment linked to increased pup corticosterone. However, the effects of LB on attachment-like behavior have not been investigated in mice where additional genetic and molecular tools are available. Furthermore, no group has utilized home-cage monitoring to link abnormal maternal care with deficits in attachment-like behavior. Using home-cage monitoring, we confirmed a robust increase in maternal fragmentation among LB dams. Abnormal maternal care was correlated with elevated corticosterone levels on post-natal day seven (P7) and a stunted growth trajectory that persisted later in life. LB did not alter maternal buffering at P8 or maternal preference at P18, indicating that certain attachment-like behaviors remain unaffected despite exposure to high levels of erratic maternal care. However, LB pups vocalized less in response to maternal separation at P8, did not readily approach their dam at P13, and exhibited higher anxiety-like behavior at P18, suggesting that LB induces avoidant-like attachment deficits in mice. Significance StatementThe impoverished conditions of limited bedding and nesting (LB) cause erratic maternal care and elevated corticosterone levels in rat and mouse pups. The increase in corticosterone levels causes attachment-like deficits in rat pups; however, it remains unclear whether similar deficits are observed in mice, where additional genomic and molecular tools are available. Using continuous home-cage monitoring, we confirmed a substantial increase in erratic maternal care and elevated corticosterone levels in 7-day-old mouse pups. LB mouse pups exhibited attachment-like deficits in some, but not all, tests, underscoring the robustness of this evolutionarily conserved bond. Despite some similarities, the attachment abnormalities observed in mice differed from previous reports in rats, paving the way for in-depth mechanistic studies in mice.

neuroscience↗

bioRxiv2025

Age-specific regulation of sociability by hypothalamic Agrp neurons

Social isolation enhances sociability, suggesting that social behavior is maintained through a homeostatic mechanism. Further, mammalian social needs shift dramatically from infancy through adolescence into adulthood, raising the question of whether the neural mechanisms governing this homeostatic regulation evolve across developmental stages. Here, we show that agouti-related peptide (Agrp) neurons, which regulate hunger in adults, are activated by social isolation from weaning through adolescence but not in adulthood. Importantly, the activity of these neurons is critical for social behavior during adolescence: inhibiting Agrp neurons reduced isolation-induced sociability in juveniles but not in adults, and Agrp neuron activation promoted sociability only in young mice. After isolation, reunion with siblings or other conspecifics, but not unfamiliar adult males, rapidly decreased neuronal activity in juveniles, an effect requiring intact olfaction. These findings identify Agrp neurons as a key component of the circuitry governing age-specific social homeostasis.

neuroscience↗

bioRxiv2024

SqueakOut: Autoencoder-based segmentation of mouse ultrasonic vocalizations

Mice emit ultrasonic vocalizations (USVs) that are important for social communication. Despite great advancements in tools to detect USVs from audio files in the recent years, highly accurate segmentation of USVs from spectrograms (i.e., removing noise) remains a significant challenge. Here, we present a new dataset of 12,954 annotated spectrograms explicitly labeled for mouse USV segmentation. Leveraging this dataset, we developed SqueakOut, a lightweight (4.6M parameters) fully convolutional autoencoder that achieves high accuracy in supervised segmentation of USVs from spectrograms, with a Dice score of 90.22. SqueakOut combines a MobileNetV2 backbone with skip connections and transposed convolutions to precisely segment USVs. Using stochastic data augmentation techniques and a hybrid loss function, SqueakOut learns robust segmentation across varying recording conditions. We evaluate SqueakOuts performance, demonstrating substantial improvements over existing methods like VocalMat (63.82 Dice score). The accurate USV segmentations enabled by SqueakOut will facilitate novel methods for vocalization classification and more accurate analysis of mouse communication. To promote further research, we release the annotated 12,954 spectrogram USV segmentation dataset and the SqueakOut implementation publicly.

neuroscience↗

bioRxiv2023

Immune sensing of food allergens promotes aversive behaviour

In addition to its canonical function in protecting from pathogens, the immune system can also promote behavioural alterations1-3. The scope and mechanisms of behavioural modifications by the immune system are not yet well understood. Using a mouse food allergy model, here we show that allergic sensitization drives antigen-specific behavioural aversion. Allergen ingestion activates brain areas involved in the response to aversive stimuli, including the nucleus of tractus solitarius, parabrachial nucleus, and central amygdala. Food aversion requires IgE antibodies and mast cells but precedes the development of gut allergic inflammation. The ability of allergen-specific IgE and mast cells to promote aversion requires leukotrienes and growth and differentiation factor 15 (GDF15). In addition to allergen-induced aversion, we find that lipopolysaccharide-induced inflammation also resulted in IgE-dependent aversive behaviour. These findings thus point to antigen-specific behavioural modifications that likely evolved to promote niche selection to avoid unfavourable environments.

immunology↗

bioRxiv2022

POMC neurons modulate infant vocalizations through opioid signaling

Infants cry when separated from their mothers. Here, we show that POMC neurons in the arcuate nucleus of the hypothalamus--via {beta}-endorphin production and signaling--modulate the crying behavior of mouse pups. The effect of POMC neurons on vocal behavior depends on the expression of {micro}-opioid receptors, the main receptor for {beta}-endorphin. Thus, POMC neurons in the hypothalamus modulate infant cry through opioid signaling.

animal behavior and cognition↗

bioRxiv2021

Deficiency of the paternally inherited gene Magel2 alters the development of separation induced vocalization in mice

The behavior of offspring results from the combined expression of maternal and paternal genes. Genomic imprinting silences some genes in a parent-of-origin specific manner, a process that, among all animals, occurs only in mammals. How genomic imprinting affects the behavior of mammalian offspring, however, remains poorly understood. Here, we studied how the loss of the paternally inherited gene Magel2 in mouse pups affects the emission of separation-induced ultrasonic vocalizations (USV). Using quantitative analysis of more than one hundred thousand USVs, we characterized the rate of vocalizations as well as their spectral features from postnatal days 6 to 12 (P6-P12), a critical phase of mouse development during which pups fully depend on the mother for survival. Our analyses show that Magel2 deficient offspring emit separation-induced vocalizations at lower rates and with altered spectral features. We also show that dams display altered behavior towards their own Magel2 deficient offspring. In a test to compare the retrieval of two pups, dams retrieve wildtype control pups first and faster than Magel2 deficient offspring. These results suggest that the loss of Magel2 impairs the expression of separation-induced vocalization in pups as well as maternal behavior, both of which support the pups growth and development.

neuroscience↗

bioRxiv2020

Ketogenesis restrains aging-induced exacerbation of COVID in a mouse model

Increasing age is the strongest predictor of risk of COVID-19 severity. Unregulated cytokine storm together with impaired immunometabolic response leads to highest mortality in elderly infected with SARS-CoV-2. To investigate how aging compromises defense against COVID-19, we developed a model of natural murine beta coronavirus (mCoV) infection with mouse hepatitis virus strain MHV-A59 (mCoV-A59) that recapitulated majority of clinical hallmarks of COVID-19. Aged mCoV-A59-infected mice have increased mortality and higher systemic inflammation in the heart, adipose tissue and hypothalamus, including neutrophilia and loss of {gamma}{delta} T cells in lungs. Ketogenic diet increases beta-hydroxybutyrate, expands tissue protective {gamma}{delta} T cells, deactivates the inflammasome and decreases pathogenic monocytes in lungs of infected aged mice. These data underscore the value of mCoV-A59 model to test mechanism and establishes harnessing of the ketogenic immunometabolic checkpoint as a potential treatment against COVID-19 in the elderly. Highlights - Natural MHV-A59 mouse coronavirus infection mimics COVID-19 in elderly. - Aged infected mice have systemic inflammation and inflammasome activation - Murine beta coronavirus (mCoV) infection results in loss of pulmonary {gamma}{delta} T cells. - Ketones protect aged mice from infection by reducing inflammation. eTOC BlurbElderly have the greatest risk of death from COVID-19. Here, Ryu et al report an aging mouse model of coronavirus infection that recapitulates clinical hallmarks of COVID-19 seen in elderly. The increased severity of infection in aged animals involved increased inflammasome activation and loss of {gamma}{delta} T cells that was corrected by ketogenic diet.

immunology↗

bioRxiv2020

ANALYSIS OF ULTRASONIC VOCALIZATIONS FROM MICE USING COMPUTER VISION AND MACHINE LEARNING

AO_SCPLOWBSTRACTC_SCPLOWMice emit ultrasonic vocalizations (USV) to transmit socially-relevant information. To detect and classify these USVs, here we describe the development of VocalMat. VocalMat is a software that uses image-processing and differential geometry approaches to detect USVs in audio files, eliminating the need for user-defined parameter tuning. VocalMat also uses computational vision and machine learning methods to classify USVs into distinct categories. In a dataset of >4,000 USVs emitted by mice, VocalMat detected more than >98% of the USVs and accurately classified {approx}86% of USVs when considering the most likely label out of 11 different USV types. We then used Diffusion Maps and Manifold Alignment to analyze the probability distribution of USV classification among different experimental groups, providing a robust method to quantify and qualify the vocal repertoire of mice. Thus, VocalMat allows accurate and highly quantitative analysis of USVs, opening the opportunity for detailed and high-throughput analysis of this behavior.

animal behavior and cognition↗

bioRxiv2016

Rapid shift in substrate utilization driven by hypothalamic Agrp neurons

Agrp neurons drive feeding. To what extend these neurons participate in the regulation of other homeostatic processes is not well understood. We investigated the role of Agrp neurons in substrate utilization in mice. Activation of Agrp neurons was sufficient to rapidly increase RER and carbohydrate utilization, while decreasing fat utilization. These metabolic changes were linearly correlated with carbohydrates ingested, but not protein or fat ingestion. However, even in the absence of ingestive behaviors, activation of Agrp neurons led to changes in substrate utilization in well-fed mice. These effects were coupled to metabolic shifts towards lipogenesis. Inhibition of fatty acid synthetase (FAS) blunted the effects of Agrp neurons on substrate utilization. Finally, Agrp neurons controlled peripheral metabolism, but not food intake, via {beta}3-adrenergic receptor signaling in fat tissues. These results reveal a novel component of Agrp neuron-mediate metabolism regulation that involves sympathetic activity on fat compartments to shift metabolism towards lipogenesis.

physiology↗