information being transmitted and the origin and termination of its connections, respectively. More recently, both neuroanatomical and electrophysiological characterizations of neural circuits have incorporated biochemical and molecular biological information in order to develop a more comprehensive portrayal of the essential qualities of a circuit that relate to its role in brain function. The key biochemical attributes of a given circuit or cell class are largely a reflection of the particular gene expression patterns, dynamics of protein synthesis, degradation and distribution, and selective activation of signaling cascades that are predominant in the neurons that furnish the circuit. The resultant biochemical profile essentially represents the neurochemical phenotype of a circuit or cell class. Operationally, one might define neurochemical phenotype as the complement of specific molecules, particularly proteins and their enzymatic products, that are enriched in and utilized by a given class of neurons in a manner that is not shared by other cell classes. The neurochemical phenotype of a neuron includes molecules related to synaptic transmission (e.g., receptors, neurotransmitters, and related enzymes), structural attributes, metabolic processes, or any characteristic that is uniquely well developed in that neuron and critically important to its designated role in brain function.

For example, a cortical neuron that uses GABA, the major inhibitory neurotransmitter, has a neurochemical phenotype that differs in many fundamental ways from a cortical neuron that uses glutamate, the major excitatory neurotransmitter. As implied in the definition of neurochemical phenotype, gene expression and protein distribution patterns are not uniform across the brain or even across a single brain region. In fact, brain circuits are highly heterogeneous with respect to which genes are expressed over time and space, and the intracellular distribution of gene products (i.e., proteins) is highly regulated. Therefore, a comprehensive neuroanatomic analysis of a circuit must address its particular neurochemical profile as well as its anatomic connections, since both will impact that circuit's functional characteristics and role in behavior.

With respect to the task at hand, the goal is to link age-related shifts in neurochemical phenotype and neuroanatomic characteristics in key cortical and hippocampal circuits to functional decrements in memory that occur with aging. Why place the emphasis for studies of aging on cell classes and circuits rather than on brain regions? More specifically, if memory is the issue and the hippocampus is critical to memory, why not address the issue of age-related pathology at the level of the entire hippocampus, rather than isolated cells, circuits, and synapses?

As described below, there are important reasons to identify and consider the brain region of interest as an important step in such analyses. However, the main rationale for bringing the analysis to a higher level of resolution and focusing on distinct cell classes and circuits is that it more accurately reflects



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