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The development of behavioral abnormalities in the motor neuron degeneration (mnd) mouse
Valerie J Bolivar1, J Scott Ganus, Anne Messer
1Wadsworth Center, New York State Department of Health, David Axelrod Institute, 120 New Scotland Avenue, P.O. Box 22002, Albany, NY 12201, USA.
Abstract:
The motor neuron degeneration (mnd) mouse, which has widespread abnormal accumulating lipoprotein and neuronal degeneration, has a mutation in CLN8, the gene for human progressive epilepsy with mental retardation (EPMR). EPMR is one of the neuronal ceroid lipofuscinoses (NCLs), a group of neurological disorders characterized by autofluorescent lipopigment accumulation, blindness, seizures, motor deterioration, and dementia. The human phenotype of EPMR suggests that, in addition to the motor symptoms previously categorized, various types of progressive behavioral abnormalities would be expected in mnd mice. We have therefore examined exploratory behavior, fear conditioning, and aggression in 2-3 month and 4-5 month old male mnd mice and age-matched C57BL/6 (B6) controls. The mnd mice displayed increased activity with decreased habituation in the activity monitor, poor contextual and cued memory, and heightened aggression relative to B6 controls. These behavioral deficits were most prominent at 4-5 months of age, which is prior to the onset of gross motor symptoms at 6 months. Our results provide a link from the mutation via pathology to a quantifiable multidimensional behavioral phenotype of this naturally occurring mouse model of NCL.
Insights
The motor neuron degeneration (mnd) mouse model exhibits early behavioral deficits, including altered activity, memory impairment, and increased aggression, before motor symptoms appear. This study quantifies these progressive neurological changes in mnd mice, linking CLN8 mutation to a complex behavioral phenotype.
Area of Science:
- Neuroscience
- Genetics
- Animal Models
Background:
- Neuronal ceroid lipofuscinoses (NCLs) are neurodegenerative disorders.
- Progressive epilepsy with mental retardation (EPMR) is a human NCL linked to CLN8 mutations.
- The motor neuron degeneration (mnd) mouse model carries a CLN8 mutation, exhibiting lipoprotein accumulation and neuronal degeneration.
Purpose of the Study:
- To investigate the behavioral phenotype of mnd mice.
- To assess exploratory behavior, memory, and aggression in mnd mice.
- To correlate behavioral deficits with the CLN8 mutation and NCL pathology.
Main Methods:
- Behavioral testing of 2-3 and 4-5 month old male mnd mice and C57BL/6 controls.
- Utilized activity monitors for exploratory behavior and habituation.
- Assessed contextual and cued fear conditioning and measured aggression levels.
Main Results:
- mnd mice showed increased activity and reduced habituation compared to controls.
- Significant deficits in contextual and cued memory were observed in mnd mice.
- Heightened aggression was noted in mnd mice, with deficits most pronounced at 4-5 months, preceding gross motor symptoms.
Conclusions:
- The CLN8 mutation in mnd mice leads to a multidimensional behavioral phenotype.
- Behavioral abnormalities manifest before overt motor deficits, offering an early indicator of NCL progression.
- mnd mice serve as a valuable model for studying NCL pathogenesis and potential therapeutic interventions.