TopicNeuroscience

murine model

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SeminarNeuroscience

Mechanisms Underlying the Persistence of Cancer-Related Fatigue

Elisabeth G. Vichaya

Baylor University

May 23, 2023

Cancer-related fatigue is a prominent and debilitating side effect of cancer and its treatment. It can develop prior to diagnosis, generally peaks during cancer treatment, and can persist long after treatment completion. Its mechanisms are multifactorial, and its expression is highly variable. Unfortunately, treatment options are limited. Our research uses syngeneic murine models of cancer and cisplatin-based chemotherapy to better understand these mechanisms. Our data indicate that both peripherally and centrally processes may contribute to the developmental of fatigue. These processes include metabolic alterations, mitochondrial dysfunction, pre-cachexia, and inflammation. However, our data has revealed that behavioral fatigue can persist even after the toxicity associated with cancer and its treatment recover. For example, running during cancer treatment attenuates kidney toxicity while also delaying recovery from fatigue-like behavior. Additionally, administration of anesthetics known to disrupt memory consolidation at the time treatment can promote recovery, and treatment-related cues can re-instate fatigue after recovery. Cancer-related fatigue can also promote habitual behavioral patterns, as observed using a devaluation task. We interpret this data to suggest that limit metabolic resources during cancer promote the utilization of habit-based behavioral strategies that serve to maintain fatigue behavior into survivorship. This line of work is exciting as it points us toward novel interventional targets for the treatment of persistent cancer-related fatigue.

SeminarNeuroscienceRecording

Understanding and treating epilepsy in tuberous sclerosis complex

Angelique Bordey

Yale University

May 5, 2021

Tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are caused by mutations in mTOR pathway genes leading to mTOR hyperactivity, focal malformations of cortical development (fMCD), and seizures in 80-90% of the patients. The current definitive treatments for epilepsy are surgical resection or treatment with everolimus, which inhibits mTOR activity (only approved for TSC). Because both options have severe limitations, there is a major need to better understand the mechanisms leading to seizures to improve life-long epilepsy treatment in TSC and FCDII. To investigate such mechanisms, we recently developed a murine model of fMCD-associated epilepsy that recapitulates the human TSC and FCDII disorders. fMCD are defined by the presence of misplaced, dysmorphic cortical neurons expressing hyperactive mTOR – for simplicity we will refer to these as “mutant” neurons. In our model and in human TSC tissue, we made a surprising finding that mutant neurons express HCN4 channels, which are not normally functionally expressed in cortical neurons, and increased levels of filamin A (FLNA). FLNA is an actin-crossing linking molecule that has also multiple binding partners inside cells. These data led us to ask several important questions: (1) As HCN4 channels are responsible for the pacemaking activity of the heart, can HCN4 channel expression lead to repetitive firing of mutant neurons resulting in seizures? (2) HCN4 is the most cAMP-sensitive of the four HCN isoforms. Does increase in cAMP lead to the firing of mutant neurons? (3) Does increase in FLNA contribute to neuronal alterations and seizures? (4) Is the abnormal HCN4 and FLNA expression in mutant neurons due to mTOR? These questions will be discussed and addressed in the lecture.

murine model

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Mechanisms Underlying the Persistence of Cancer-Related Fatigue

Understanding and treating epilepsy in tuberous sclerosis complex

COMPARATIVE THERAPEUTIC EFFICACY OF AAV9-GALC AT DIFFERENT INJECTION TIME POINTS AND PROMOTERS IN THE TWITCHER MURINE MODEL OF KRABBE DISEASE

<EM>IN VIVO</EM> ADENINE BASE EDITING-MEDIATED CORRECTION OF <EM>GALC</EM> GENE MUTATION AMELIORATES DISEASE PROGRESSION IN A MURINE MODEL OF KRABBE DISEASE

BRAIN: 3D CHARACTERIZATION OF BRAIN VASCULATURE AND MICROGLIA TO UNCOVER MORPHO-PHYSIOLOGICAL ALTERATIONS IN ALZHEIMER’S DISEASE MURINE MODELS

BASIS OF PHYSIOPATHOLOGY IN A NOVEL MURINE MODEL OF AUTOSOMAL DOMINANT RETINITIS PIGMENTOSA TYPE 10 BY MUTATIONS IN INOSINE MONOPHOSPHATE DEHYDROGENASE 1

THE IMPACT OF ISCHEMIC LESION ON THE CELLULAR MICROENVIRONMENT AND LONG-TERM NEUROBEHAVIORAL OUTCOMES IN A NOVEL MURINE MODEL OF PEDIATRIC STROKE

DECIPHERING NEUROTROPIC MECHANISMS OF BURKHOLDERIA SPECIES: GENOMIC INSIGHTS AND MURINE MODEL DEVELOPMENT

MEAL TIMING MODULATES COGNITIVE FUNCTION AND CIRCADIAN NEUROBIOLOGY VIA THE GUT MICROBIOTA: HUMAN EVIDENCE AND TRANSLATIONAL FINDINGS IN MURINE MODELS

DEVELOPING A MURINE MODEL OF CEREBRAL VENOUS THROMBOSIS FOR PRECLINICAL RESEARCH

VASCULAR DYSREGULATION AND BLOOD-BRAIN BARRIER IMPAIRMENT IN A MURINE MODEL OF NEURODEGENERATION

COLLAGEN, BEYOND THE SCAFFOLD: EXPLORING BRAIN VULNERABILITY IN THE <EM>BRTL</EM> MURINE MODEL

DIFFERENTIAL EFFECTS OF OUABAIN ON BDNF EXPRESSION IN LUNG AND BRAIN IN A MURINE MODEL OF MIXED ASTHMA

REPEATED TOLUENE EXPOSURE EXACERBATES MOTOR RESPONSES IN A MURINE MODEL OF PARKINSON’S DISEASE

D-SERINE REFLECTS INTRATHECAL INFLAMMATION IN MULTIPLE SCLEROSIS AND COUNTERACTS MOTOR IMPAIRMENT IN A MURINE MODEL

STUDY OF THE EFFECTS OF RIMEGEPANT IN A MURINE MODEL OF ENDOMETRIOSIS AND MIGRAINE COMORBIDITY

SEX-DEPENDENT RESPONSES TO THE FAT-TASTE ENHANCER NKS-3 IN A MURINE MODEL OF DIET-INDUCED OBESITY

INVESTIGATING THE BLOOD-CSF BARRIER IN ALZHEIMER’S DISEASE: AΒ TRANSPORT AND BARRIER INTEGRITY IN A TRIPLE TRANSGENIC MURINE MODEL

NEUROPROTECTIVE EFFECTS OF <EM DATA-START="544" DATA-END="562" >MORINGA OLEIFERA</EM> AGAINST MPTP-INDUCED DOPAMINERGIC NEURODEGENERATION IN A MURINE MODEL

Correlation between motoneuronal survival and VEGF expression in brainstem motoneurons in the SOD1 ALS murine model

Ex-vivo and in-vivo analysis of hippocampal pathology in a murine model of anti-GABAB autoimmune encephalitis

Characterization of the nitrergic system in the VPA murine model of autism

Gene expression alterations in the hippocampus of a murine model of Prader-Willi syndrome

Description of post-traumatic brain lesion in a pediatric murine model of injury

Development of novel rabbit monoclonal antibodies to characterize microglial activation states in murine models of Alzheimer’s disease

Effect of high-fat diet on hippocampal synaptic transmission and plasticity and neuroinflammation in a murine model of Amyotrophic Lateral Sclerosis

Newly synthesized fatty acid analogue (NKS-3) rescues microglial reactivity in a murine model of diet-induced obesity

Electrophysiological and behavioral characterization of murine model exposed to acute sarin sublethal doses and antidote therapy evaluation

GSK-3β inhibitor, VP3.15, restores cognitive impairment and neuronal compromise in a murine model of intraventricular hemorrhage of the preterm newborn

Heterotopia subtype-specific morpho-electric and connectivity properties underlie distinct dynamics of epileptiform activity in murine models of grey matter heterotopia

Impact of vagal nerve stimulation on the progression of demyelinated lesions in a murine model of multiple sclerosis

Osteogenesis imperfecta: A look into the brain of a murine model

Vascular alterations in mixed murine models of metabolic disorders and Alzheimer´s disease

Prediabetes and type 2 diabetes affect tau phosphorylation patterns in murine models of Alzheimer’s disease

NVU alterations explain motivational deficits in a murine model of chronic distress

Characterization of peripheral and brain-specific innate immune responses in a murine model of NMDAR encephalitis