Spatial working memory (WM; i.e., "scratchpad" memory) is constantly updated to guide behavior based on representational knowledge of spatial position. It is maintained by spatially tuned, recurrent excitation within networks of prefrontal cortical (PFC) neurons, evident during delay periods in WM tasks. Stimulation of postsynaptic alpha2A adrenoceptors (alpha2A-ARs) is critical for WM. We report that alpha2A-AR stimulation strengthens WM through inhibition of cAMP, closing Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels and strengthening the functional connectivity of PFC networks. Ultrastructurally, HCN channels and alpha2A-ARs were colocalized in dendritic spines in PFC. In electrophysiological studies, either alpha2A-AR stimulation, cAMP inhibition or HCN channel blockade enhanced spatially tuned delay-related firing of PFC neurons. Conversely, delay-related network firing collapsed under conditions of excessive cAMP. In behavioral studies, either blockade or knockdown of HCN1 channels in PFC improved WM performance. These data reveal a powerful mechanism for rapidly altering the strength of WM networks in PFC.

Summary In this review, we discuss how working memory prefrontal cortical (PFC) circuits are modulated differently than plastic changes in sensory/motor and subcortical circuits. Working memory arises from recurrent excitation within layer III PFC pyramidal cell NMDA circuits, which are afflicted in aging and schizophrenia. Neuromodulators rapidly and flexibly alter the efficacy of these synaptic connections, while leaving the synaptic architecture unchanged, a process called Dynamic Network Connectivity (DNC). Increases in calcium-cAMP signaling open ion channels in long, thin spines, gating network connections. Inhibition of calcium-cAMP signaling, e.g. by noradrenergic α2A-adrenoceptor stimulation on spines, strengthens synaptic efficacy and increases network firing, while optimal levels of dopamine D1 receptor stimulation sculpt network inputs to refine mental representation. Generalized increases in calcium-cAMP signaling during fatigue or stress disengage dlPFC recurrent circuits, reduce firing and impair top-down cognition. Impaired DNC regulation contributes to age-related cognitive decline, while genetic insults to DNC proteins are commonly linked to schizophrenia.

The aging rhesus macaque provides the long-sought animal model for exploring the etiology of late-onset Alzheimer's disease and for testing preventive strategies.

Prefrontal cortical (PFC) working memory functions depend on pyramidal cell networks that interconnect on dendritic spines. Recent research has revealed that the strength of PFC network connections can be rapidly and reversibly increased or decreased by molecular signaling events within slender, elongated spines, a process we term Dynamic Network Connectivity (DNC). This newly discovered form of neuroplasticity provides great flexibility in mental state, but also confers vulnerability and limits mental capacity. A remarkable number of genetic and/or environmental insults to DNC signaling cascades are associated with cognitive disorders such as schizophrenia and age-related cognitive decline. These insults may dysregulate network connections and erode higher cognitive abilities, leading to symptoms such as forgetfulness, susceptibility to interference, and disorganized thought and behavior. Vulnerabilities in prefrontal cortical networksThe cognitive operations of the prefrontal cortex (PFC) are especially vulnerable to physiological, genetic and environmental factors; they are altered by changes in arousal state such as fatigue or stress [1], they decline early in the aging process [2], and are profoundly impaired in most mental illnesses [3][4][5]. PFC cognitive functions rely on networks of interconnecting pyramidal cells [6]. New research is revealing that PFC network connections are influenced by powerful molecular events that determine whether a network is connected or disconnected at a given moment, thus determining the strength of cognitive abilities [7,8]. These mechanisms provide great flexibility, but also confer vulnerabilities and limit mental capacity. A remarkable number of genetic and/or environmental insults to these molecular signaling cascades are associated with cognitive disorders such as schizophrenia and age-related cognitive decline. These insults may dysregulate network connections and weaken higher cognitive abilities. In this article, we describe some of the molecular events that can rapidly alter PFC network strength, a process we call Dynamic Network Connectivity (DNC). We propose that DNC may be considered a novel form of very rapid plasticity that coordinates momentary changes in the state of arousal with appropriate cognitive network operations. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptTrends Cogn Sci. Author manuscript; available in PMC 2011 August 1. PFC networks subserving representational knowledgeThe PFC is able to represent information that is not currently in the environment through n...