Physiology
SECTION 4: CIRCUITS Appetitive Signaling
glial cells are discussed in this section on the immune system, because some of their functions are relevant to the immune system.) Microglia are the brain’s resident macrophages. Macrophages are a type of white blood cell that can phagocytize (eat) debris. The microglia play a vital role in cleaning up old synapses and remodeling the brain. They also play a big role in brain inflammation, which may be a problem in those with depression. When the microglia are not activated to fight infection, they play a role in maintaining brain health (Kettenmann, Kirchhoff, &
Verkhratsky, 2013; Littrell, 2012; Parkhurst et al., 2013).
Astrocytes are the second type of glial cell in the brain. They have receptors for glutamate (the major excitatory neurotransmitter). By detect-ing glutamate release, they can release factors that will impact blood ves-sels, resulting in a shift of blood flow to more active brain areas (Nolte, 2009). They also play a role in storing glucose and getting this fuel (in the form of lactic acid) to very active neurons. One particular theory regard-ing the cause of ADHD holds that the astrocytes are sluggish in their performance of this function (Killeen et al., 2013).
Oligodendrocytes are support cells that wrap around the axons of neurons and allow for faster movement of neurotransmitter packets down an axon. In multiple sclerosis, for example, oligodendrocytes are destroyed (Nolte, 2009).
SECTION 4: CIRCUITS
mate bonding (Young & Alexander, 2014). As stated in Section 2, this sys-tem is about motivation (wanting but not necessarily liking), about paying attention to the environment, and learning the connections between stim-uli and consequences (the incentive salience system). The system strongly activates behavior as well. It is known that when this system is activated, the animal will be more lively. Locomotion and exploration are increased (Hyman, Malenka, & Nestler, 2006; Nestler & Carlezon, 2006).
In addition to activating to opportunities for sex and food, reward areas in people (the ventral striatum area in which the nucleus accum-bens is located) are also activated by social cues. Research participants who read statements of love and appreciation from their friends and relatives showed activation in the reward areas. Being treated fairly and seeing others treated fairly activates this area. Additionally, these struc-tures activate when someone else who has been treated unfairly now gets rewarded (Lieberman, 2013).
As discussed in Section 2, the appetitive signaling pathway is not always about enjoyable activities. When an animal engages in vigor-ous activity in response to negative aversive stimuli or positive stim-uli, the nucleus accumbens is activated. The basal amygdala (area of the brain that registers fear) projects to the nucleus accumbens.
When an animal runs away from an aversive stimulus, the nucleus accumbens is activated (Hartley & Phelps, 2010), although not when an aversive stimuli does not require action (as when viewing unpleasant imagery; Lang & Bradley, 2010). The nucleus accumbens can be activated when working for food as well as when the animal works to avoid shock (Lang & Bradley, 2010). In fact, various areas in the nucleus accumbens are active when responding to aversive cues, whereas other areas of the brain respond to approach stimuli (Berridge & Kringelbach, 2013). Observations of bereaved individu-als longing for deceased spouses have individu-also noted activation of the nucleus accumbens (O’Connor et al., 2008).
Turning Off Activity in the Nucleus Accumbens
The lateral habenula plays a strong role in inhibiting the neurons in the VTA that project to the nucleus accumbens (Hikosaka, 2010; Hong, Jhou, Smith, Saleem, & Hikosaka, 2011; Lammel et al., 2012). The lateral
habenula is active given the absence of an expected reward and when the animal is subjected to uncontrollable shock (Hikosaka, 2011; Stamatakis et al., 2013; Figure 2.9).
As will be discussed in the text on learned helplessness that follows, uncontrollable shock initiates activity in the lateral habenula, which acti-vates anxiety structures and suppresses the VTA.
Creating Learned Helplessness
In the 1970s, Steven Maier, Marty Seligman, and Bruce Overmier developed a paradigm called learned helplessness. Learned helpless-ness has been characterized as a laboratory model for depression and/
or anxiety. The paradigm entails subjecting an animal to uncontrol-lable shock delivery. The animals in the control condition experience the same level of shock intensity for the same duration, but unlike the animal that has learned helplessness, the animals in the control group can turn off the shock.
Both escapable and inescapable shocks induce some of the same com-ponents of anxiety. Both increase stress hormone release (the release of cortisol), reduce activity, reduce exploration in an open field, and reduce sucrose preference (Christianson et al., 2008; Maier & Watkins, 2010).
However, inescapable shock induces additional components of anxi-ety. Animals that have been subjected to uncontrollable shock exhibit a reduction in food and water intake, a reduction in social interaction, a reduction in swimming when placed in water, a reduction in aggression and social dominance, and exaggerated fear. When learned-helpless ani-mals are moved to another environment where they can turn off shock, they fail to exert control. They have effectively learned helplessness. They have given up (Maier & Watkins, 2005, 2010).
Neural Circuitry
The neural circuitry involved in learned-helpless behavior has been articulated. However, in keeping with the wide variety of behaviors that are associated with learned helplessness, the neural circuitry has several branches. The habenula begins the response to inescapable shock. The habenula projects to two regions: the VTA and the caudal part of the
FIGURE 2.9 Lateral habenula.
The solid circle in the top image is the lateral habenula. C, caudate; CC, corpus callosum;
Hc, habenular commissure; IC, inferior colliculus; LHb, lateral habenula; MD, mediodor-sal nucleus of the thalamus; MHb, medial habenula; N3, oculomotor nucleus; PC, poste-rior commissure; PT, pretectum; Pul, pulvinar; SC, supeposte-rior colliculus; Th, thalamus.
Source: Hikosaka (2007; modified 2011).
Th SC
IC
Cerebellum cc
C Cerebral cortex
CC
MD
PT hc
pc MHb
N3 Pul
LHb
dorsal raphe nucleus. The caudal part of the dorsal raphe nucleus (which contains serotonergic neurons) projects to two regions: the amygdala and the striatum (Forgeard et al., 2011; Hale et al., 2012; Strong et al., 2011). We will look at each branch in turn.
The Habenula to the Caudal Dorsal Raphe
The habenula sends projections to the caudal part of the dorsal raphe nucleus in the brain stem, activating this structure (Amat et al., 2001).
The causal dorsal raphe nucleus, with its serotonergic neurons, is critical to the learned-helpless response. If the caudal dorsal raphe structure is lesioned, then learned helplessness cannot be induced (Maier & Watkins, 2005, 2010).
Creating Anxiety/Fear
The caudal part of the dorsal raphe projects to the basolateral amygdala.
The basolateral amygdala projects to other areas of the amygdala, which eventually activate other brain areas (such as the hypothalamus and PAG), resulting in the physiology of anxiety and freezing behavior (Christianson et al., 2010; Maier & Watkins, 2010; Strong et al., 2011). A critical output area of the amygdala is through the bed nucleus of the stria terminalis (BNST). Lesions of the BNST preclude failure to escape after exposure to inescapable shock, whereas lesions of other parts of the amygdala do not (Forgeard et al., 2011; Hammack, Richey, Watkins, &
Maier, 2004; Maier & Watkins, 2010).
The BNST is again discussed in the chapter on anxiety (Chapter 5).
Although the amygdala is about fear, the BNST is about anxiety, or being ready to be fearful (see Chapter 5, “Anxiety”). A learned-helpless animal is anxious and will exhibit enhanced fear to the next fear stimulus pre-sentation (Maier & Watkins, 2005, 2010).
Motor Behavior Changes
The caudal part of the dorsal raphe nucleus also projects to the dorsal stri-atum (which influences motor behavior). The caudal dorsal raphe nucleus projection to the dorsal striatum projection establishes the escape deficits and may play a role in facilitating freezing behavior (Strong et al., 2011).
The lateral habenula is an initiating structure in producing the syn-drome of learned helplessness. In addition to projecting to the caudal
part of the dorsal raphe nucleus, the lateral habenula also projects to the VTA, inhibiting activity in the VTA. The result is that activity is further decreased. These connections probably are responsible for the anhedonia (lack of motivation and lack of response to reward) observed in learned-helpless animals (B. Li et al., 2011; Y. Li et al., 2013).
Creating a Resilient Animal
There are several ways to create resilient animals. In resilient animals, exposure to uncontrollable shock fails to induce anxiety symptoms and
“giving up.” Both exercise and exposure to controllable stress will create resilience. The mechanisms for creating resilience are known but each differs in terms of how it works.
Researchers have known that animals that have prior experience with controllable shock are less susceptible to becoming learned helpless when later exposed to uncontrollable shock. Researchers have examined which brain structures are recruited during the exposure to controllable stressors. During exposure to controllable shock, the ventromedial PFC sends projections to excite the GABA interneurons in the caudal dorsal raphe nucleus. (Recall that GABA inhibits the neurons onto which they synapse.) The GABA interneurons inhibit the firing of serotonergic neu-rons during the initial exposure to controllable shock (Maier & Watkins, 2010). For those animals that have an initial encounter with controllable shock, the ventromedial PFC is again recruited when, subsequently, the previously controllable shock becomes uncontrollable. (See Figures 2.5 and 2.7 for various areas in the PFC.) The ventromedial PFC will effec-tively tame the learned helplessness structures (the caudal dorsal raphe nucleus) when the animal is later exposed to uncontrollable shock. The experimenters did do a little bit more experimenting to prove their point.
If the ventromedial PFC neurons are prevented from firing in the resilient animals, then the resilient animals are no longer immune to the effects of uncontrollable shock. Knocking out the ventromedial PFC neurons will wipe out resilience. Without the ventromedial neurons, learned helpless-ness in response to uncontrollable shock occurs even in those animals with prior experience with controllable shock (Maier & Watkins, 2010).
The ventromedial PFC is a pretty important area for restraining distress.
As we will see in the chapter on anxiety (Chapter 5), the ventromedial PFC
is also important for inhibiting the amygdala (area of the brain activated by fright) when learned fears are extinguished. Learned resilience has many ramifications. The resilience evoked by exposure to controllable shock is a generalized resilience. Those exposed to escapable shock also are less impaired when subsequently exposed to social defeat. Although resilient animals respond normally to an unconditioned fear stimulus (such as the scent of a cat), they less readily develop a conditioned fear response. Moreover, in resilient animals, previously learned conditioned fears decline to a greater extent during extinction training (Maier &
Watkins, 2010).
Second Way to Create Resilience
There is another strategy for creating resilience. If animals are given access to the running wheel before exposure to uncontrollable shock, they are far less likely to become learned helpless. Greenwood et al. (2011, 2012) have identified the mechanism through which exercise creates resilient mice. As stated previously, the caudal dorsal raphe nucleus is a key struc-ture in the circuit resulting in learned helplessness. The serotonin from the caudal part of the dorsal raphe nucleus synapses onto receptors in the amygdala and the dorsal striatum. Exercise will decrease the presence of serotonin receptors in both of these structures. Thus, when the serotonin is released, there are fewer receptors available to receive the message.
Helplessness in response to inescapable shock is less likely to occur. Just as in the animals, exercise is known to decrease both anxiety and depres-sion in humans (Herring, O’Connor, & Dishman, 2010; Saeed, Antonacci, &
Bloch, 2010; Strohle, 2009).
Regulation of Impulses, Motor Activity, and Emotions
The PFC is often referred to as the area of executive control. In the previous section on resilience, we encountered the ventromedial PFC, which directly inhibits the serotonergic neurons in the caudal part of the dorsal raphe to block learned helplessness. In the chapter on anxiety (Chapter 5), we will again talk about the ventromedial PFC because it plays a vital role in unlearn-ing learned fears by directly inhibitunlearn-ing the amygdala. Here, we will be look-ing at a few more additional regions in the PFC that may be involved in other types of restraint: the dorsolateral and the ventrolateral PFC.
Some caveats need to be stated. The PFC is more developed in humans than in other animals. Much of the work on the ventromedial PFC was done on animals, where connections between neurons can be traced. In contrast to animal work, exploration of emotional and behavioral regula-tion in people is done with imaging. In order to ask about which brain areas influence each other, researchers must rely on imaging of the brain as a research participant does something. Researchers investigate which areas of the brain are active or inactive at the same time. If one area is active while another area is inactive, an inference regarding one area’s inhibiting another might be drawn. Human research can also use a tech-nique called “diffusion tensor imaging” to trace the degrees of axonal connectivity between areas. Unfortunately, inferences from imaging work can fail to inform more precisely how one region might influence another.
There could be a direct connection; alternatively, one region could influ-ence another through a third connection. Neuroscientist Elizabeth Phelps (2006) works with animals and people. Phelps cautions that the ventro-lateral PFC, which plays an active role in recasting emotionally evocative stimuli, does not have a direct connection in animals with the amygdala (a region involved in fear and anxiety). In people, the ventrolateral PFC may influence the amygdala through the ventromedial PFC.
Inhibiting responses across a wide variety of domains involve some of the same brain structures: a specific area in the ventrolateral PFC (the infe-rior frontal gyrus pars opercula, which is also referred to as Area 44), the ventromedial PFC (Aron, Robbins, & Poldrack, 2004; Jovanovic &
Norrholm, 2011; Ochsner, Silvers, & Buhle, 2012), and the dorsolateral PFC (Sokol-Hessner, Camerer, & Phelps, 2013; Urry et al., 2006).
The ventrolateral PFC (more specifically, the inferior frontal gyrus) is activated when drug addicts inhibit cravings, when anyone represses the performance of a previously learned motor response, when repressing strongly associated cognitions (e.g., the moon is associated with night, and the sun with day), and when suppressing emotional reactions to grotesque photos (Tabibnai et al., 2011). Based on human-imaging work, the ventrolateral PFC (again, more specifically the inferior frontal gyrus) inhibits regions involved in motor output (the subthalamic nucleus that controls basal ganglia output), that is, when a person wants to restrain a response (Aron et al., 2004). Some imaging studies also suggest that dur-ing the process of a delay-of-gratification task, the ventromedial PFC is again involved in inhibiting activity in the nucleus accumbens (Diekhof &
Gruber, 2010; Diekhof et al., 2011). A recent study found that when the dorsolateral PFC is inhibited with electrical stimulation, people consume more junk food and perform more poorly on a task requiring inhibition of an impulsive first response (Lowe, Hale, & Staines, 2014).
The role of the lateral PFC in inhibiting first responses (prepotent responses) on tasks has been demonstrated in a variety of ways. Goel and Dolan (2003) gave people valid syllogisms, which, however, started with false premises. People were asked whether the inference from the false premise was true. The question was whether the deduction followed from the syllogism, not whether the deduction (conclusion) was false.
Thus, people had to inhibit saying “false” to an obviously wrong conclu-sion because it was a logical deduction from the premise. This is hard to do; one has to suppress the first, more spontaneous response. On those trials in which individuals were able to exert the cognitive control, more activity in the right lateral PFC was noted. Elsewhere, it has been dem-onstrated that when transcranial magnetic stimulation is used to scram-ble the ventrolateral PFC, then people commit more errors (Verbruggen, Aron, Stevens, & Chambers, 2010).
The PFC is also involved in controlling negative emotions. For sup-pressing anxiety, the ventrolateral, dorsolateral, and the ventromedial PFC may all be involved. In studies in which research participants were asked to reappraise or think about a distressing image in a less provoca-tive way, increased activity in the ventrolateral PFC is found (Ochsner, Bunge, Gross, & Gabrieli, 2002; Wagner, Davidson, Hughes, Lindquist, &
Ochsner, 2008). In a particular study examining responses as people thought about distressing images in less provocative ways, there was decreased activity in the amygdala that was inversely correlated with activity in the PFC (Eippert et al., 2007). In another study, people were distracted from their reactions to distressing images by having to make non–emotion-related judgments. In the distracting task, a decrease in amygdala activity was associated with an increase in ventral PFC activity (Hariri, Mattay, Tessitore, Fera, & Weinberger, 2003). Other studies find that the dorsolateral PFC and the ventromedial PFC are activated when altering amygdala activation to negative images or to contemplating the possibility of loss (Sokol-Hessner et al., 2012; Urry et al., 2006).
In addition to the amygdala being activated in response to distress-ing stimuli, the dACC becomes active in response to both physical pain and the social pain associated with rejection. The PFC is involved in
regulation of the dACC as well as other anxiety structures. When people are exposed to social rejection or experience physical pain, strong acti-vation in the ventrolateral PFC is correlated with less actiacti-vation of the dACC, suggesting that the ventrolateral PFC can suppress the dACC in response to physical pain or social rejection (Lieberman, 2013; Lieberman &
Eisenberg, 2009). In addition to activation in the brain’s distress areas, stress hormones spike when people are disturbed. When people are subjected to looking at emotional photographs, more activity in the ventromedial PFC is correlated with less stress hormone release (Shin & Liberzon, 2010). Across studies then, the dorsolateral, ventrolateral, and the ventromedial PFC play roles in suppressing distress areas of the brain (Hartley & Phelps, 2010).
In the 1970s, Walter Mischel carried out the now famous marshmal-low study with 4-year-olds at Stanford University (Mischel, Ebbesen, &
Raskoff-Zeiss, 1972). These 4-year-olds were given a choice of ringing a bell and receiving one marshmallow now or waiting for the experimenter to return and receiving two marshmallows. Basically, the marshmallow experiment was a test of delay of gratification. Later follow-up on the chil-dren who had delayed gratification found that they were distinguished by higher Scholastic Aptitude Test scores and grade point averages (Eigste et al., 2006). When imaged as adults in the scanner, they exhibited more activity in the right ventrolateral PFC than others (Casey et al., 2011). Thus, delay of gratification depends on structures in the PFC.
Additional findings also suggest that regulatory control capacity extends to multiple domains. Those who score high on measures of persistence show greater activity in the ventromedial PFC and regard more images as pleasant than other people viewing the same images (Gusnard et al., 2003).
In a short-term study, researchers found that intentionally inhibiting a motor response enhanced capacity for dampening amygdala activity while watching an emotional face (Berkman, Burklund, & Lieberman, 2009).
The research reviewed in this section suggests that the PFC is involved in regulating behaviors and emotions across a variety of domains, includ-ing downregulatinclud-ing intense negative emotions, delayinclud-ing gratification, inhibiting motor impulses, and inhibiting thoughts. Self-regulation will be relevant for recovery from substance abuse as well as regulating nega-tive emotions (namely, anxiety and sadness). Self-regulation is not a static, immutable trait. Roy Baumeister has suggested that areas of the brain involved in regulation of emotions and impulses function like a muscle (discussed more in Chapter 8). The strength of these areas can be enhanced
by practice over time. For example, in an experimental study, attending to one’s posture increased ability to resist temptation. Using the nondomi-nant hand in daily routines increased the ability to maintain smoking abstention (Heatherton & Wagner, 2011). In addition to increasing regu-latory control through practice, it may be possible to increase reguregu-latory control by increasing heart rate variability (HRV). This pathway will be discussed in a later section on the autonomic nervous system (Section 5).
Putting It All Together: bAS and bIS
Psychologists have developed the concepts of the behavioral activation system (BAS) and behavioral inhibition system (BIS). The terms were originated by Jeffrey Grey in the 1970s, who examined fear responding in animals. These terms were adopted by Richie Davidson in the late 1980s; he postulated that the right PFC cortex activity was more heavily connected with the BIS, whereas activity on the left PFC cortex activity reflected activity in the BAS. In fact, in imaging studies, the right PFC (the medial region of the right oribitofrontal cortex [OFC]) is responsive to punishment, whereas the left PFC (medial region of the OFC) is more active during reward (Davidson, Pizzagalli, Nitschke, & Putnam, 2002).
Across studies, operationalization of the BAS and the BIS is done in mul-tiple ways. Davidson measured EEG activity differentials between the right and left sides of the head. (EEG is a crude measure of electrical activity in the cortex.) In 1994, Carver and White published paper-and-pencil scales designed to assess the BAS and BIS. These paper-and-pencil measures did correlate as expected with measures of the differential left versus right elec-trical activity measured by EEG (Amodio, Master, Yee, & Taylor, 2008).
Research categorizing individuals as high on the BIS has found that the measures do relate to behavior in the predicted manner. Early on, Davidson measured electrical activity in the two hemispheres of the brain. Davidson found that an infant’s greater right side electrical activity during stranger approach was correlated with more crying, with greater stress hormone (cortisol) output, and predicted subsequent shyness at tod-dler age (Buss et al., 2003; Davidson & Fox, 1989). This work was consistent with previous findings in primates on how hemispheric activity related to behavior (Buss et al., 2003). Subsequent research used the paper-and-pencil measure to identify those with strong BIS. When shown images of
angry people, those with high BIS scores showed greater activation of the distress area (dorsal anterior cingulate) than others (Beaver, Lawrence, Passamonti, & Calder, 2008).
Research examining how operationalization of measures of the BAS relates to personality traits has been consistent with the predictions of Davidson: Those who score high on the BAS system are less fearful and more active. People who score high on measures of BAS are much less likely to be intimidated and more likely to be activated in response to aggression. When shown anger images, those with high score on the BAS show activation in the amygdala, but less activation in an area of the brain associated with distress (dorsal anterior cingulate; Beaver et al., 2008).
Preliminary evidence does link high BAS levels with greater dop-amine function in the nucleus accumbens under conditions of oppor-tunity for reward. There is also suggestion that high BAS scorers have less dopamine function in the PFC, an area that might dampen the nucleus accumbens (Wacker, Mueller, Pizzagalli, Hennnig, &
Stemmier, 2013).
Activity in the left PFC can also be used as a measure of a momen-tary state. Greater activity in the left PFC is associated with more activity in the nucleus accumbens, the appetitive structure (Davidson & Irwin, 1999; Sutton, Larson, Holden, Perlman, & Davidson, 1997). (Recall that the activity in the nucleus accumbens is about making an active response.) On being provoked, left-brain activity increases in those who are in a position to retaliate relative to those who cannot take action (Harmon-Jones, Lueck, Fearn, & Harmon-(Harmon-Jones, 2006).
Emotional Inhibition/Regulation in High BAS Scorers
It should be noted that the term inhibition is used in two different ways in the literature. Inhibition can refer to inhibiting active behavior as seen in shy people. Inhibition can refer to regulating emotional behavior, includ-ing fear responses. Those with strong BAS are less behaviorally inhibited as the term is used to describe shy or fear-subdued individuals; however, they are better at regulating (inhibiting) distress.
A number of observations suggest that those with strong BAS are bet-ter at emotional regulation. Those who display greabet-ter left-brain activity (those who are high on the BAS) deny any negative affect (Tomarken &
Davidson, 1994). They demonstrate decreased attention to and memory for negative stimuli (Tomarken & Keener, 1998). They exhibit less star-tle to a loud noise after being told to suppress their feelings to previ-ously viewed distressing pictures (Davidson, 1998; Davidson et al., 2000).
Those with high BAS scores are higher on measures of emotional control (increased HRV discussed in the section on the parasympathetic nervous system; see Section 5) and higher in the ability to inhibit motoric behavior on a stop-signal task (Sütterlin, Anderson, & Vögele, 2011).
Another researcher, George Bonanno, has been examining those with strong BAS, although he did not set out to do so. Bonanno has spent much of his career examining how people respond to bereavement. Bonanno has identified people who deny distress at the time of bereavement but who show strong activation in terms of their heart rates and sweaty palms.
He labels these individuals as repressors. Other researchers have found that those who deny any negative affect are higher on left PFC activity (Tomarken & Davidson, 1994), suggesting that Bonanno’s subjects have a strong BAS. Bonanno’s findings attest to the benefits of having a strong BAS. Those who are repressors at the time of bereavement not only report less distress at the time of the loss of a loved one, but they also show bet-ter future recovery (Coifman, Bonanno, Ray, & Gross, 2007).
The meaning of the BAS concept is explored more thoroughly in the chapter on bipolar disorders (Chapter 7).