Thesis Abstract

<p> </p><div><p>              <b>ABSTRACT</b><br></p><p>The prefrontal cortex occupies the anterior portion of the frontal lobes and is thought to be one of the most complex anatomical and functional structures of the mammalian brain. Its major role is to integrate and interpret inputs from cortical and sub-cortical structures and use this information to develop purposeful responses that reflect both present and future circumstances. This includes both action-oriented sequences involved in obtaining rewards and inhibition of behaviors that pose undue risk or harm to the individual. Given the central role in initiating and regulating these often complex cognitive and behavioral responses, it is no surprise that alcohol has profound effects on the function of the prefrontal cortex. In this chapter, we review the basic anatomy and physiology of the prefrontal cortex and discuss what is known about the actions of alcohol on the function of this brain region. This includes a review of both the human and animal literature including information on the electrophysiological and behavioral effects that follow acute and chronic exposure to alcohol. The chapter concludes with a discussion of unanswered questions and areas needing further investigation.</p></div><div><strong>Keywords </strong>Executive function, Orbitofrontal cortex, Working memory, Persistent Activity, Up-States</div> <br><p></p>

Thesis Overview

<p><b>1.1 INTRODUCTION&nbsp;</b></p><p> It is now widely accepted that alcohol and other addictive drugs act within the mesolimbic dopamine (DA) system of the brain. This system originates in the ventral tegmental area (VTA) and projects to various limbic structures, including the nucleus accumbens (NAc), amygdala, and hippocampus. Most notably, it is thought that the positive reinforcing effects of drugs of abuse relate to enhanced DA neurotransmission particularly within the NAc. Therefore, virtually all models of the addiction neurocircuitry feature the mesolimbic DA system as central to the addictive process. However, evidence gained over the past decade or more suggests that drug-induced changes in the prefrontal cortex (PFC) also critically regulate drug and alcohol addiction (Everitt and Robbins, 2005; Kalivas and Volkow, 2005; Kalivas, 2009). This evidence comes from diverse studies that include human and animal behavioral work, brain imaging, electrophysiology, and molecular and cellular observations. Whereas a comprehensive review of the role of the PFC in addiction is beyond the scope of this chapter, our aim is to provide a review of the literature regarding the effects of acute and chronic alcohol exposure on PFC structure and function. Consistent with the accumulating evidence implicating the PFC in addiction to opiates, cocaine, and other psychostimulants, it is our contention that current models of the neurocircuitry of alcohol addiction should prominently include ethanol-induced alterations in PFC structure and function. We further suggest that long-lasting alterations in the executive function of the PFC and its associated networks may play an equal or even greater role in alcohol addiction and relapse to drinking than changes within the mesolimbic DA system. <br></p><p> <b>II. Anatomy of the Prefrontal Cortex&nbsp;</b></p><p>The cerebral cortex of humans and nonhuman primates is separated into a frontal and posterior region by the Rolandic fissure. The primary motor cortex (area 4) is a relatively narrow cortical area that lies immediately anterior to this fissure, and immediately anterior to the primary motor cortex is the premotor cortex (area 6). The PFC makes up the remaining anterior pole of the frontal cortex (Fig. 1, shaded area) and is divided into three interconnected subregions known as the lateral PFC, the medial/cingulate PFC, and the orbital PFC (commonly referred to as the orbitofrontal cortex (OFC)). Although overlapping but not identical, the term ventromedial PFC is sometimes encountered in the literature instead of OFC. The PFC was originally termed the “frontal granular cortex” based upon the presence of a cortical granular layer IV and a location rostral to the agranular premotor cortex. However, subsequent comparisons across species of other cortical areas with known functional homology soon revealed that defining cortical regions based upon a granular versus agranular cytoarchitecture was invalid, and current definitions of the PFC utilize functional homology and anatomical connectivity across species. With regard to connectivity, the presence of dense reciprocal projections between the mediodorsal nucleus of the thalamus along with certain cortico-cortical connections is now considered the major defining structural feature of the PFC that is applicable to all mammalian species (Fuster, 2008). While it must be kept in mind that there are generally no neat boundaries separating the subregions of the PFC, the human PFC can be grossly localized to specific Brodmann areas of the frontal cortex. The lateral PFC is composed principally of parts or all of Brodmann areas 8, 9, 10, and 46, and the medial PFC is composed principally of parts of areas 8, 9, 10, and 12, with areas 24, 25, and 32 forming the anterior cingulate (ACC). The orbitofrontal cortex (OFC) is the ventral portion of the frontal cortex on the dorsal surface of the orbit and is comprised of areas 11, 12, 13, and 14. The PFC is extensively interconnected not only between cortical layers but also between subregions, and this connectivity helps to define distinct neural networks that exert behavioral control. The portion of the lateral PFC dorsal to the fundus of the principal sulcus receives afferent projections mainly from the medial PFC and belongs to the dorsolateral PFC network, whereas that portion that lies ventral to the principal sulcus receives afferent projections mostly from the OFC and belongs to the ventrolateral (sometimes referred to as orbitoventral) PFC network (Barbas and Pandya, 1989; Ongur and Price, 2000). In addition to reciprocal connections with the thalamus, the lateral PFC is connected either directly or indirectly with virtually all areas of the neocortex and hippocampus and has dense efferent projections to the dorsal caudate nucleus (e.g., dorsal striatum). There are distinct medial and orbital PFC networks that are also characterized by cortico-cortical connections and connections with brain regions outside the PFC. The medial PFC is connected with the thalamus and sends efferents to the hypothalamus and periaqueductal gray, and belongs to a network that plays a major role in autonomic and somatic responses to emotional stimuli. The ACC receives similar reciprocal projection as the medial PFC but is thought to belong to a network involved in attentional processing and conflict monitoring. The OFC is densely connected with the basal ganglia, amygdala, and other prefrontal areas, and belongs to a network that mediates motivational and affective aspects of behavior. The medial and OFC networks are sometimes grouped together as the orbitomedial PFC (OMPFC). The medial PFC and OFC are phylogenetically older regions, whereas the lateral PFC is a phylogenetically newer structure and provide substrates for executive cognitive functions. The role of the PFC in behavioral control is discussed in greater detail in the following section. <br></p><p> The extent to which rats have a PFC has been the subject of debate (Uylings et al., 2003; Seamans et al., 2008). The main issue of controversy is whether rats have a prefrontal area that is comparable with the dorsolateral PFC of primates. In their review of the extant human, nonhuman primate, and rodent literature, Uylings et al. (2003) concluded that, similar to primates, rodents do in fact have a region of the frontal cortex that can be defined both anatomically and functionally as PFC. They provide a strong argument that rats have a functionally divided prefrontal cortex that includes not only features of the medial and orbital areas in primates, but also some features of the primate dorsolateral PFC. In a more recent review, Seamans et al. (2008) took this a step further by suggesting that the rat medial PFC combines elements of the primate dorsolateral PFC and ACC at a rudimentary level that in primates may have formed the building blocks required for abstract rule encoding during evolutionary expansion of the PFC dorsally. <br></p><p> As in primates, the rodent PFC is located in the anterior pole of the frontal cortex and is loosely defined as the ACC, the medial PFC, and the OFC, as well as portions of the agranular insular cortex. The rodent medial PFC is subdivided into a dorsally located prelimbic mPFC (PrL-mPFC) and ventrally located infralimbic mPFC (IfL-mPFC) subregion. The OFC is also subdivided into the medial, ventral, lateral, and dorsolateral orbitofrontal regions. The connectivity of the rodent PFC has common features with that of primates, including a dorsal-to-ventral gradient of projection patterns. For example, the PrLmPFC sends dense projections to the dorsal striatum that transitions to the ventral stratum (nucleus accumbens) as one moves ventrally through the IfL-mPFC to the OFC. <br></p><p> <b>III. The Executive Function of the Prefrontal Cortex&nbsp;</b></p><p>The perception–action cycle, originally described by Arbib in 1985, is a behavioral construct of circular information flow that describes the interaction of an organism with its environment allowing it to carry out the orderly sequencing of goal-directed actions (Arbib, 1985). As pointed out by Fuster (2008), an important element of this construct is that it includes internal feedback from effectors to sensors to provide representations of current actions to sensory structures to modulate further input. In anatomical terms, there are two cognitive networks of this cycle (Fuster, 2008). One is the perceptual network of the posterior cortex and the other is the executive network of the frontal cortex. Although these networks are structurally distinct, they are not functionally independent and there is a great deal of information exchange between them. Furthermore, the cortical components of these networks do not act independent of subcortical structures. At the apex of the hierarchical organization of the perception–action cycle is the PFC. <br></p><p> Before proceeding further with a discussion of executive function, we should note there are different models of cognitive networks of the PFC. Prominent are variations of modular concepts where cognitive representations are essentially ascribed to different neural connections and anatomical locations (e.g., localization of working memory to the dorsolateral PFC) (Norman and Shallice, 1986). In contrast is the model of large-scale cortical networks first suggested by Bressler and expanded upon by Fuster (Bressler, 1995; Fuster, 2008). In this model, while cognitive networks may have foci, to one degree or another, in specific subregions of the PFC, they are widely distributed and bind together neuronal assemblies from widespread regions of the cortex during information processing. Importantly, a network can subserve different cognitive needs (e.g., memories), and different neurons or groups of neurons can participate in, or belong to, different networks depending upon the particular ongoing cognitive demands. The formation of these networks is presumably dependent upon attractor dynamics of cell assemblies that encode specific actions or memories. <br></p><p> The primary function of the PFC can be summarized as the temporal organization of behavior. Executive function involves attention, planning, and decision making, and is how the PFC organizes behavior in a sequential manner. This occurs in large part through the dynamic interaction of two parallel networks of the PFC—an “executive” network with a primary location in the dorsolateral PFC (or medial PFC in rodents) and a “limbic” network primarily contained in the OFC (Fig. 2). These networks mediate higher-order behaviors such as purposeful goal-directed actions, language, and reasoning. These networks are required to perform a number of functions for appropriate control of goal-directed behavior (outlined by Moghaddam and Homayoun, 2008). In summary, they must (1) detect situations that demand mediation, (2) direct selective attention to stimuli relevant to this situation, (3) suppress distractions caused by irrelevant stimuli, (4) bring on line relevant past memories, (5) plan behavioral sequence based upon these memories and the present relevant stimuli, and (6) encode the preparatory set that leads to motor execution of the appropriate behavior. As noted above, the executive network is thought to be primarily localized within the dorsolateral PFC, and as such this structure is considered to be the ultimate regulator of goal-directed actions. However, the ACC also critically contributes to many aspects of executive functioning by mediating attention to action and conflict monitoring. Also as noted previously, the OFC is extensively connected with sensory cortical areas and limbic structures, and it is thought that this network plays a role in integrating and determining the salience of information about environmental contingencies. It plays a particularly important role in inhibitory control of inappropriate behaviors by relaying processed information to the executive control network of the dorsolateral PFC. Thus, the executive and limbic networks function in concert to orchestrate behaviors particularly related to context and expected outcomes (e.g., expectation of a goal-directed action). <br></p><p> Any discussion of the executive function of the PFC would be remiss without at least mentioning working memory, one of the major executive cognitive functions of the PFC. Working memory is a form of sustained attention for the processing of prospective action. Thus, working memory involves the maintenance and manipulation of task-relevant information in the service of planning, problem solving, and predicting forthcoming events (Unterrainer and Owen, 2006; D’Esposito, 2007). Working memory is therefore a form of “active” memory involving sustained attention that is focused on an internal representation and can be distinguished from short-term memory. Although short-term memory often functions in the service of working memory (e.g., bringing a short-term memory online for the purpose of planning and predicting forthcoming events), it is classically viewed as temporary memory storage prior to its storage in long-term memory. Closely related to working memory is attentional “set”, which is essentially attention to motor activity and is used to plan a sequence of forthcoming actions. In a sense, working memory is the representation of the near past whereas set is a representation of the near future (Fuster, 2008), and together they are critical for the temporal organization of behavior.</p><p>Glutamatergic neurotransmission is the primary regulator of activity-dependent synaptic modifications that underlie experience-dependent brain plasticity (Chandler, 2003). As will be discussed in the next section, both acute and chronic alcohol exposure significantly impact glutamatergic neurotransmission in the PFC. In addition, results from several studies suggest that plastic processes of associative learning overlap and interact with those that underlie the development of addictive behaviors (Berke and Hyman, 2000). Addiction is clearly a complex disease that involves motivational and higher-order cognitive processes that initiate and control goal-directed behaviors, and accumulating evidence implicates altered glutamatergic neurotransmission mediated by projections to and from the prefrontal cortex in the neuroplasticity of addiction (Jentsch and Taylor, 1999; Kalivas, 2009). The PFC is highly integrated into the addiction neurocircuitry. Addictive behaviors, such as those associated with alcohol abuse and alcoholism, include loss of control over consumption and relapse to drinking. The PFC normally exerts “top-down” (e.g., information derived from prior experience) inhibitory control over internal and external sensory-driven compulsive behaviors. Increasing evidence suggests that continued drug exposure leads to attenuation of the ability of the PFC to monitor and inhibit these behaviors, with eventual loss of inhibitory control over drinking. Volkow and colleagues have conceptualized this loss of inhibitory control by the PFC as a syndrome of “impaired response inhibition and salience attribution” (Goldstein and Volkow, 2002; Volkow et al., 2003). This syndrome is envisioned to encompass an integrated cluster of addictive behaviors that depend upon interaction with the PFC. An important feature of the PFC is that it is functionally and structurally adaptable, and a major component of cortical cognitive processing is that it is highly influenced by “knowledge” of past experiences. Thus, reward information such as that provided by the VTA dopaminergic system has a pervasive and lasting influence on the activity of the PFC. <br></p>