Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Con el presente estudio se pretende entregar una herramienta válida en el campo de la neuropsicología, de modo que pueda servir a los que trabajan en esta área clínica y que constantemente se ven sometidos a la difícil tarea de aportar desde este campo a los diagnósticos diferenciales. Como esta investigación constituye una primera mirada a la ejecución de los sujetos considerados normales frente a las distintas pruebas objeto de esta investigación, se espera que sirva como parámetro inicial para la futura obtención de normas. También se espera que esta investigación se transforme en una herramienta útil para futuras investigaciones en el área de la neuropsicología y más específicamente dentro del área de los trastornos disejecutivos, que sin duda siguen siendo los trastornos ampliamente cuestionados, tanto en su presentación como en su evaluación.

With advancing age, many cognitive faculties deteriorate, and navigation abilities may be among those most affected. The majority of previous work investigating navigation impairments in ageing has focused on allocentric processing, attributing deficits to hippocampal dysfunction. However, real-world navigation is dependent upon numerous different strategies, as well as the ability to flexibly switch between them. Outside the context of navigation, it has been demonstrated that strategy switching, thought to be coordinated by regions of prefrontal cortex and the locus coeruleus-noradrenergic system, is also susceptible to the effects of ageing. Deficits in navigational strategy switching, and prefrontal or noradrenergic dysfunction, are therefore also likely to contribute to age-related navigation impairments. The work presented in this thesis aimed to explore age-related impairments in strategy switching within the context of navigation, and the underlying neural mechanisms in terms of a prefrontal-noradrenergic model of switching. The studies presented in Chapter Three assessed the use of allocentric and egocentric navigational strategies by young and older people. Older participants tended to use an egocentric strategy where an allocentric strategy was required, possibly due to a difficulty in switching to the appropriate allocentric strategy. In Chapter Four, I provide an account of two studies directly assessing navigational strategy switching, using two different tasks based in virtual reality. The first study utilised a virtual adaptation of the plus maze task, involving switching between an allocentric place strategy and an egocentric response strategy, and demonstrated that older participants were specifically impaired at switching to the place strategy. The second study used a more realistic task set in a virtual town environment, which involved switching from an egocentric route-following strategy to an allocentric wayfinding strategy, and also demonstrated an age-related deficit in switching to an allocentric strategy. In Chapter Five, I begin to explore the mechanisms underlying impaired navigational strategy switching in ageing. Firstly, I describe a further behavioural study that used variants of the virtual plus maze and a navigational gambling task to demonstrate a contribution of impaired decision making to the deficit in switching to an allocentric strategy. This indicates that the deficit can be attributed, at least in part, to prefrontal dysfunction. A second study presented in the same chapter demonstrated that practising orienteering does not protect against decline in navigational strategy switching ability with ageing. Chapter Six provides an account of my direct assessment of the neural bases of navigational strategy switching using functional magnetic resonance imaging. In young subjects, I found some evidence in support of the roles of prefrontal regions in navigational strategy switching. However, I was unable to complete development of a task suitable for assessing age differences in functional activation of brain regions involved in navigational strategy switching. The final experimental study, included in Chapter Seven, assessed pupil size and heart rate as physiological correlates of noradrenergic activity during performance of the virtual plus maze. Both young and old participants demonstrated a noradrenergic response to all strategy changes, suggesting that impairments are more likely attributable to dysfunction of prefrontal cortex than of the locus coeruleus, although some subtle effects suggested that noradrenergic dysfunction does have some effect on navigational strategy switching deficits. In the same chapter, I report the results of a meta-analysis of data from five of the preceding studies, suggesting that deficits in both strategy switching and allocentric processing combine to produce a greater impairment in switching to an allocentric strategy. The main finding of this series of studies is that navigational strategy switching is impaired in ageing, which may contribute to the more widely reported difficulties that older people have with navigation. My work also provides evidence in support of a prefrontal-noradrenergic model of navigational strategy switching, and suggests that dysfunction of prefrontal cortex and, to a lesser extent, the locus coeruleus-noradrenergic system is responsible for decline in navigational strategy switching ability with ageing. In conclusion, this thesis draws attention to the important role of deficient executive processing and dysfunction of extra-hippocampal brain regions in age-related navigation impairments.

Processing information related to the self and inferring the mental state of another person is known to involve the ventromedial prefrontal cortex (VMPFC) in both younger and older adults (Stone et al., 2008; Kelley et al., 2002; Hynes et al., 2006; Ruby et al., 2009). According to the dorsolateral prefrontal (DLPF) theory of cognitive ageing, processing of the self should not be affected by healthy adult ageing as functions related to the VMPFC remain relatively preserved compared to functions related to the DLPF cortex (MacPherson et al., 2002). Similarly, no age difference should emerge in those tasks thought to tap functions of the VMPFC. The aim of this PhD is to investigate the effect of healthy adult ageing on the ability to process information related to the self and others. A series of experiments was designed to compare the performance of younger and older adults on tasks that investigate processing and retrieval of self-related information (e.g. behaviour prediction, personality judgement, mental state inferences, self-referential). The tasks differ in the extent to which they rely on cognitive effort. The results show that ageing does not affect self-related judgements. A further series of experiments designed to investigate affective and cognitive Theory of Mind (ToM) show that the affective performance, thought to rely on VMPFC activity, is not affected by age. In contrast, the performance of older participants differs from that of younger adults on cognitive ToM task, thought to involve DLPFC brain areas. A final experiment investigated the ability to make self versus other related judgments in a confabulating patient. The results show that the ability to reflect on the self but not on others was intact. In summary, the findings demonstrate that processing self-information and making ToM inferences remains intact in older individuals and is not overtly impaired by confabulation.

The current project examined the ability of nicotine to modulate dopamine transporter (DAT) function. Initial experiments determined the dose-response for nicotine to modulate dopamine (DA) clearance in rat striatum and medial prefrontal cortex (MPFC) using in vivo voltammetry and determined if this effect was mediated by nicotinic receptors (nAChRs). In both striatum and MPFC, nicotine increased DA clearance in a mecamylamine-sensitive manner, indicating nAChR-mediation. The effect of acute nornicotine on DAT function was also determined. In contrast to nicotine, nornicotine in a dose-related manner decreased striatal DA clearance in a mecamylamine-sensitive manner, indicating nAChR mediation. To determine if tolerance developed to the nicotine effect nicotine, separate groups of rats were injected once daily for 5 days with nicotine or saline. DA clearance in striatum and MPFC was determined 24 hrs after the last injection. Nicotine increased DA clearance only 10-15% in the group repeatedly administered nicotine, demonstrating that tolerance developed. To determine if nicotine altered striatal DAT efficiency, following nicotine injection, DAT density and maximal velocity of [3H]DA uptake was determined using [3H]GBR12935 binding and saturation analysis of [3H]DA uptake in rat striatum, respectively. Nicotine did not alter the Bmax or Kd of maximal binding of [3H]GBR12935 binding. However, an increase in Vmax was observed at 10 and 40 min following nicotine injection, suggesting that nicotine increases DAT efficiency. To determine if systemic nicotine enhanced DAT function via an action at nAChRs on striatal DA terminals, [3H]DA uptake was determined in striatum in vitro in the absence or presence of nicotine in the buffer. Nicotine did not alter the Vmax for [3H]DA uptake in vitro, suggesting that the nicotine-induced increase in DAT function observed in vivo is mediated by nAChRs on DA cell bodies or another site which indirectly alters DAT function. To determine if the increase in DAT efficiency was due to increased surface expression of striatal DAT, biotinylation and Western blot analyses were performed. Nicotine did not alter striatal DAT, suggesting that the nicotine-induced increase in DA clearance in vivo and DAT efficiency in vitro is not the result of increased trafficking of this protein to the cell surface.

The prefrontal cortex (PFC) is an area of the brain that is critically important for learning, memory, organization, and integration, and PFC dysfunction has been associated with pathologies including Alzheimer’s disease, schizophrenia, and drug addiction. However, there exists a paucity of information regarding neurochemical signaling in the distinct sub-regions of the PFC, particularly the medial prefrontal cortex (mPFC). The mPFC receives glutamatergic input from a number of brain areas, and functional glutamate signaling is essential for normal cognitive processes. To further understand glutamate neurotransmission, in vivo measurements of glutamate were performed in the cingulate cortex, prelimbic cortex, and infralimbic cortex of anesthetized rats using enzyme-based microelectrode array technology. Measurements of acetylcholine were also performed to examine the relationship between glutamate and other neurotransmitters in the mPFC. The described studies revealed a homogeneity of glutamate and acetylcholine signaling in the mPFC sub-regions, indicating somewhat uniform tonic and phasic levels of these two transmitters. In the infralimbic mPFC of awake freely-moving rats, rapid, phasic glutamate signaling events, termed “transients” were observed and in vivo glutamate signaling was successfully monitored over 24 hour time periods. The effects of methylphenidate (MPH), a stimulant medication with abuse potential that is used in the treatment of attention-deficit hyperactivity disorder, were measured in mPFC sub-regions of anesthetized rats. Data revealed similar tonic and phasic glutamate levels between chronic MPH-treated rats and controls in all sub-regions. Locomotor data from the chronic treatment period supported the behavioral sensitization effects of multiple MPH treatments. Significant effects were observed in locomotor activity, resting levels of glutamate, and glutamate uptake rates in the infralimbic mPFC of awake, freely-moving animals that received chronic MPH treatment. Taken together, this body of work characterizes glutamate signaling in the rat mPFC to a degree never before reported, and serves to report for the first time the effects of MPH on glutamate signaling in the mPFC.

The medial prefrontal cortex (mPFC) plays a critical role in the organization of goal directed behavior. This role is suggested by the anatomy of mPFC as the region rests at the top of a complex cortical and sub-cortical hierarchy, receives convergent sensory and motor information from multiple modalities, and is the target of modulatory brainstem nuclei that respond to prediction and reward. Given these observations, it was hypothesized that mPFC neurons store associations between stimuli when the stimuli contribute to the prediction of reward. To test this hypothesis, neural ensemble spiking activity was recorded in the mPFC as rats performed a paired-associate discrimination task. In one condition, both elements of the paired-associate stimulus-sequence provided information about reward delivery. In another condition, only the first stimulus contributed to the prediction. As hypothesized, stimulus-selective, prospective delay activity was observed during sequences in which both elements contributed to reward-prediction. Unexpectedly, however, selective delay responses were associated with slight variations in head position and thus were not necessarily generated by intrinsic mnemonic processes. Interestingly, the sensitivity of neurons to head position was greatest during intervals when reward delivery was certain. These result suggest that a major portion of delay activity in the rat mPFC reflects task-relevant sensory-motor activity, possibly related to behavioral strategies rather than to the local storage of stimulus-stimulus associations. These observations agree with evidence suggesting that mPFC neurons are particularly responsive during the performance of actions related to the acquisition of reward. These results also indicate that considerable attention must be given to the monitoring of sensory-motor variables during delay tasks as slight changes in position can produce activity that appears to be driven by intrinsic mechanisms. It is further suggested that such activity may perform an important role in memory guided behavior, although this role may contrast sharply with standard theories of delay activity and short term memory storage. In particular, it is suggested that delay activity observed in the prefrontal cortex may correspond to the maintenance of memories that are 'stored' in the body or in the environment in the forms of embodied or situated behaviors.

Recent functional neuroimaging evidence suggests that recalling autobiographical memories, imagining fictitious autobiographical episodes, and taking the perspective of another person activate a similar network of brain regions. Results from the two studies presented here provide further evidence of this common neural network. Previous evidence also suggests that recalling autobiographical memories from a first person or from a third person perspective can influence the way in which those memories are experienced as well as the brain regions that are engaged; however, the effect of perspective on imagining autobiographical events remains unclear. Results from Study 1 indicated that brain regions implicated in both remembering and imagining were differentially engaged during these tasks depending on whether a first person or a third person perspective was taken. In addition, while recalling autobiographical memories from a third person perspective can result in the feeling that a past self is more like another person, imagining oneself in the position of another person can result in the feeling that that person is more similar to oneself; this suggests a possible link between perspective in memory and social perspective taking. In Study 2, we identified several brain regions exhibiting a pattern of increasing or decreasing activation as a function of whether socially interactive events were recalled from a first person perspective, by imagining oneself as one's partner, or from a third person perspective (i.e., as a function of distance from one's own perspective). Together, our findings suggest that perspective plays an important role in the way in which brain regions that are part of this common neural network are engaged during memory, imagination, and socially interactive tasks.

"Stable multi-day recordings from chronically implanted microelectrodes within the dorsolateral prefrontal cortex of two monkeys performing three Go/NoGo visual discrimination tasks (one requiring well-learned responses, two requiring learning) demonstrated that the majority of prefrontal neurons were 'functionally stable'. Action potentials of 94 neurons were stable over 2-9 days; 66/94 (70%) of these cells responded each day, 22/94 (23%) never responded significantly, and 6/94 (6%) responded one day but not the next. Of 66 responsive neurons, 55 were selective for either Go or NoGo trials, individual stimuli, or eye movements." (Greenberg and Wilson, 2004) Selectivity was maintained, for 46/55 neurons across all recording days. Response strength (baseline vs. post-stimulation firing rates) and event-related response timing also displayed stability. Stability generalized across neuronal response type suggesting that functional stability is a general property. Long-term recordings from other studies supported similar conclusions suggesting that neurons throughout the brain are functionally stable. Single-day recordings from different neurons within the same cortical regions demonstrated neuronal response flexibility while monkeys learned associations among visual cues, and Go/NoGo behavioral responses. Of 116 neurons, 57 (49%) displayed significant change points in firing rates during novel learning (n=18), reversal learning (n=12), or both tasks (n=27). Six of 57(10.5%) neurons had firing rates changes prior to learning and might have been causally related to the monkeys' behavioral changes. However, only 18/152 (12%) of the total number of firing rate changes occurred prior to the monkeys' learning meaning that most appeared to be the consequences of learning rather than the causes.

The prefrontal cortex (PFC) is critically involved in many higher cognitive functions such as goaldirected behaviour, affective behaviour and especially working memory. In vivo extracellular recordings of PFC neural activity during working memory tasks show high variety in observed spiking patterns. These complex dynamics are critically shaped by intrinsic, synaptic and structural parameters of respective prefrontal networks. Moreover, dopamine (DA) is crucial for correct functioning of the PFC during working memory tasks. DA modulates a number of synaptic and intrinsic biophysical properties of single neurons, in particular deep layer pyramidal cells, which represent the major output neurons of the PFC. Despite a high variability of cortical pyramidal cell firing patterns, and somatodendritic morphology, no study has yet systematically examined correlations between intrinsic properties, morphological features and dopaminergic modulation of intrinsic properties. This study investigated properties of deep layer pyramidal cells through whole cell patch clamp in acute brain slices of the adult rat PFC. Cells were characterised physiologically through a variety of stimulation protocols surveying different time scales and wide intensity ranges, while all fast synaptic transmission was blocked. Furthermore the same catalogue of stimuli was recorded whilst applying specific DA receptor agonists to elucidate effects of DA receptor activation on intrinsic properties. All recorded cells were injected with biocytin and dendritic morphology was reconstructed from confocal image stacks of fluorescently labelled neurons. From the resulting data a set of characteristic variables were defined and a combination of principal components analysis and hierarchical cluster analysis was used to identify similarity between recorded cells in different parameter spaces spanned by intrinsic properties, intrinsic properties under dopaminergic modulation and morphology, respectively. The analysis presents evidence for distinct subpopulations within prefrontal deep layer pyramidal cells, as seen by clustering of recorded cells in these high dimensional parameter spaces. These subpopulations also show distinct input-output relationships, bearing implications for computational functions of these subpopulations. Furthermore, this study presents for the first time evidence of subpopulation specific DA effects in deep layer pyramidal cells. The quantitative analysis of somatodendritic morphology confirms physiological subpopulations and identifies characteristic morphological features of deep layer pyramidal cells. Moreover, cluster observed in different parameter spaces overlap, leading to a definition of subpopulations that concurs with previously described prefrontal pyramidal cell types. In conclusion, the results presented provide some deeper insight into fundamental principles of information processing in prefrontal pyramidal cells under the influence of dopamine.