Mark R. Mayford
Lab Overview
The ability to remember is perhaps the most significant and distinctive feature
of our cognitive life. Impairments in learning and memory are a component of
disorders that affect human beings throughout life, from childhood forms of
mental retardation to psychiatric disorders like Schizophrenia with onsets
in late adolescence and early adulthood to diseases of aging such as Alzheimer’s.
My lab uses genetic manipulation in mice to investigate the cellular and molecular
events that are involved in learning and memory.
Highlight
One of the difficulties in studying the underlying cellular and molecular
mechanisms of complex neurobiological processes such as learning and memory
is the difficulty in identifying and manipulating the neurons involved. In
order to address this issue we have developed transgenic mice that allow the
permanent genetic tagging of neurons that are activated in response to specific
behavior manipulations. The system is based on the cfos promoter and is designed
to allow the assessment of activity patterns (based on cfos promoter expression)
at two widely spaced time points. We have used this approach to examine the
effects of extinction training on circuit reactivation. Animals were trained
in a fear conditioning paradigm and the activated neurons were persistently
tagged with a lacZ marker to produce a record of the activity during learning.
Following varying degrees of extinction training the behavioral performance
was assessed in a recall trial, which also produced acute activation of a cfos-EGFP
transgene. Thus, in each individual animal we have a record of neuronal activity
during learning (lacZ), neuronal activity during recall (EGFP) and behavioral
performance. We found that behavioral performance was correlated with the degree
of overlap in the lacZ and EGFP signals in the lateral amygdala. This demonstrates
that the strength of memory recall is determined by the level of reactivation
of neurons initially activated during training, and that extinction degrades
the level of circuit reactivation. We have also used this approach to investigate
the memory consolidation process whereby memories become independent of the
hippocampus over prolonged periods of time. We found that over a 2-week period
following training, the pattern of neuronal activity in the hippocampus recapitulates
the activity produced by the original training. Thus, the hippocampus is replaying
the previously learned information off line. This is consistent with a model
of memory consolidation in which ongoing hippocampal activity alters the connectivity
of other brain regions allowing them to ultimately support memory recall independent
of the hippocampus.
2006 Publications
Reijmers LG, Coats JK, Pletcher MT, Wiltshire T, Tarantino LM, Mayford M.
A mutant mouse with
a highly specific contextual fear conditioning deficit found in an N-ethyl-N-nitrosourea
(ENU) mutagenisis screen. Learn Mem. 2006;13(2):143-149.
Yasuda M, Mayford M. CaMKII activation in the entorhinal cortex disrupts
previously encoded
spatial memory. Neuron 2006;50(2):309-318.
