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The prefrontal cortex is necessary for directing thought and planning action. Working memory, the active, transient maintenance of information in mind for subsequent monitoring and manipulation, lies at the core of many simple, as well as high-level, cognitive functions. Working memory has been shown to be compromised in a number of neurological and psychiatric conditions and may contribute to the behavioral and cognitive deficits associated with these disorders. It has been theorized that working memory depends upon reverberating circuits within the prefrontal cortex and other cortical areas. However, recent work indicates that intracellular signals and protein dephosphorylation are critical for working memory. The present article will review recent research into the involvement of the modulatory neurotransmitters and their receptors in working memory. The intracellular signaling pathways activated by these receptors and evidence that indicates a role for G q -initiated PI-PLC and calcium-dependent protein phosphatase calcineurin activity in working memory will be discussed. Additionally, the negative influence of calcium-and cAMP-dependent protein kinase (i.e., calcium/calmodulin-dependent protein kinase II (CaMKII), calcium/diacylglycerol-activated protein kinase C (PKC), and cAMP-dependent protein kinase A (PKA)) activities on working memory will be reviewed. The implications of these experimental findings on the observed inverted-U relationship between D 1 receptor stimulation and working memory, as well as age-associated working memory dysfunction, will be presented. Finally, we will discuss considerations for the development of clinical treatments for working memory disorders.Working memory is the capacity to temporarily keep in mind information that is not currently present to the senses in order to monitor and manipulate this information for a particular purpose. Therefore, it is the ability to keep one's thought on information acquired in the past, in light of present demands, in order to plan one's actions to reach a future goal. An example of working memory is watching for traffic as one attempts to cross the street. As one turns to cross the street, one must keep in mind the position of the oncoming traffic, while monitoring and using this information to calculate the appropriate time to initiate the attempt. The relative position of the cars is the information that is being held for the period of seconds it takes to make the decision to walk or not. Crossing the street is the goal, or purpose, that requires one's thoughts to be direct and maintained on the traffic flow. Once the information is used, it is forgotten to minimize conflicts with subsequent decisions (Dudchenko 2004). The ability to integrate different information for planning and for goal-directed, purposeful action such as decision-making and problem-solving also requires working memory. For example, when a person is presented with a problem, a series of comparative evaluations must be done in order to determine the pros and cons for ...

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Traumatic brain injury (TBI)--induced dysfunction of the prefrontal cortex causes many high-level cognitive deficits, including working memory (WM) dysfunction. WM lies at the core of many high-level functions, yet the cellular and molecular mechanisms underlying its dysfunction are poorly understood. Lesion and pharmacological studies in rodents have implicated the medial prefrontal cortex (mPFC), which includes the prelimbic/infralimbic (PL/IL) cortices, in WM tasks. These studies have shown that optimal levels of catecholamine neurotransmission are critical for normalcy of WM function, suggesting that alterations in their synthesis may play a role in WM dysfunction. Using the cortical impact injury model of traumatic brain injury which reproducibly causes working memory deficits in rodents, we have measured the protein levels and activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine biosynthesis, and tissue dopamine (DA) and norepinephrine (NE) levels in microdissected PL/IL tissues. Our results show that TBI increases TH protein levels, its activity and tissue DA and NE content in the PL/IL. These findings suggest that altered catecholamine signaling within the PL/IL may contribute to impaired PFC function, and may have implications in the design and implementation of strategies to alleviate prefrontal dysfunction in brain injury patients.

Traumatic brain injury (TBI)is a major human health concern that has the greatest impact on young men and women. The breakdown of the blood-brain barrier (BBB) is an important pathological consequence of TBI that initiates secondary processes, including infiltration of inflammatory cells, which can exacerbate brain inflammation and contribute to poor outcome. While the role of inflammation within the injured brain has been examined in some detail, the contribution of peripheral/systemic inflammation to TBI pathophysiology is largely unknown. Recent studies have implicated vagus nerve regulation of splenic cholinergic nicotinic acetylcholine receptor ␣7 (nAChRa7) signaling in the regulation of systemic inflammation. However, it is not known whether this mechanism plays a role in TBI-triggered inflammation and BBB breakdown. Following TBI, we observed that plasma TNF-␣ and IL-1␤ levels, as well as BBB permeability, were significantly increased in nAChRa7 null mice (Chrna7 Ϫ / Ϫ ) relative to wild-type mice. The administration of exogenous IL-1␤ and TNF-␣ to brain-injured animals worsened Evans Blue dye extravasation, suggesting that systemic inflammation contributes to TBI-triggered BBB permeability. Systemic administration of the nAChRa7 agonist PNU-282987 or the positive allosteric modulator PNU-120596 significantly attenuated TBI-triggered BBB compromise. Supporting a role for splenic nAChRa7 receptors, we demonstrate that splenic injection of the nicotinic receptor blocker ␣-bungarotoxin increased BBB permeability in brain-injured rats, while PNU-282987 injection decreased such permeability. These effects were not seen when ␣-bungarotoxin or PNU-282987 were administered to splenectomized, brain-injured rats. Together, these findings support the short-term use of nAChRa7-activating agents as a strategy to reduce TBI-triggered BBB permeability.

Previous reports have demonstrated that some focal brain injuries increase amyloid precursor protein (APP) immunoreactivity in the region surrounding the injury where it was localized, in damaged axons and in pre-alpha 2 cells of the entorhinal cortex. However, to date, APP expression in the hippocampus remote from the impact site has not been comprehensively studied. Therefore, we have evaluated APP expression not only in the locally injured cerebral cortex but also in the hippocampus remote from the impact site. In the present paper, diffuse axonal injury was induced in rats in midline fluid percussion injury. APP expression was examined post injury using Western blot analysis and immunohistochemistry. Western blot analysis demonstrated that the expression of 100-kd APP was increased in both the cerebral cortex and hippocampus 24 h after injury. It then decreased in the hippocampus, but did not change in the cerebral cortex, 7 days after injury. Immunohistochemical studies showed increased immunoreactivity of APP in the neuronal perikarya and reactive astrocytes near the region of injury in the cerebral cortex 24 h to 7 days after injury. In the hippocampus, APP accumulated in the CA3 neurons 24 h and 3 days after injury, although no hemorrhagic lesions were seen at that site. The APP positive neurons in CA3 showed shrunken cell bodies and pyknotic nuclei 3 days after injury, and some of the neurons in CA3 had disappeared by 7 days postinjury. The results of present study suggest that traumatic brain injury induces overexpression and accumulation of APP in neuronal perikarya and that these events are followed by degeneration of CA3 neurons. Further, the decline in APP expression in the hippocampus is thought to be due to neuronal loss in CA3 subsector.

Working memory (WM), the ability to transiently hold information in mind, is essential for high-level cognitive functions that are often impaired in brain-injured patients. The cellular and molecular mechanisms contributing to WM deficits, which can manifest in the absence of overt damage, in these patients are unknown. The function of the dorsolateral prefrontal cortex in humans and monkeys, and the medial prefrontal cortex (mPFC), in rodents is critical for WM. We demonstrate that controlled cortical impact injury of rats causes a long-lasting WM impairment that is associated with increased levels of the GABA-synthesizing enzyme glutamic acid decarboxylase 67 (GAD67) in the mPFC for up to 1 month after injury. A single administration of dopamine D 1 antagonists at 14 d after injury is sufficient to decrease GAD67 levels and restore WM for at least 1 week. These findings indicate that inhibition of prefrontal neuronal activity contributes to WM deficits and that strategies to reduce GAD67 expression can offer prolonged WM improvement in brain-injured patients.

The prefrontal cortex is highly vulnerable to traumatic brain injury resulting in the dysfunction of many high-level cognitive and executive functions such as planning, information processing speed, language, memory, attention, and perception. All of these processes require some degree of working memory. Interestingly, in many cases, post-injury working memory deficits can arise in the absence of overt damage to the prefrontal cortex. Recently, excess GABA-mediated inhibition of prefrontal neuronal activity has been identified as a contributor to working memory dysfunction within the first month following cortical impact injury of rats. However, it has not been examined if these working memory deficits persist, and if so, whether they remain amenable to treatment by GABA antagonism. Our findings show that working memory dysfunction, assessed using both the delay match-to-place and delayed alternation t-maze tasks, following lateral cortical impact injury persists for at least 16 weeks post-injury. These deficits were found to be no longer the direct result of excess GABA-mediated inhibition of medial prefrontal cortex neuronal activity. Golgi staining of prelimbic pyramidal neurons revealed that TBI causes a significant shortening of layer V/VI basal dendrite arbors by 4 months post-injury, as well as an increase in the density of both basal and apical spines in these neurons. These changes were not observed in animals 14 days-post-injury, a time point at which administration of GABA receptor antagonists improves working memory function. Taken together, the present findings, along with previously published reports, suggest that temporal considerations must be taken into account when designing mechanism-based therapies to improve working memory function in TBI patients.