Social interactions in early life influence the organization of neural and behavioural systems of developing mammalian young. Deprivation of social interactions with the primary caregiver and other immediate conspecifics (early social deprivation) has lasting consequences on behavioural functioning in later life. The purpose of this thesis was to investigate how early social deprivation affects the motivational aspects of behaviour in the context of appetitive stimuli. Rats were reared in complete isolation from the mother and litter using the method of artificial rearing (AR). Control rats were maternally reared (MR). In adulthood, rats were tested in a series of behavioural paradigms designed to assess the motivational impact of primary food reward and reward-related cues on food-seeking behaviour. AR increased the behavioural responsiveness of rats to the motivational impact of reward-related cues, but not to primary rewards themselves. Specifically, there were no significant effects of AR on food consumption or goal-directed instrumental responding for food. However, AR enhanced instrumental responding triggered by a previously conditioned reward cue. AR also increased the expression of approach behaviour towards a localizable conditioned reward cue and instrumental responding when the same cue was used as a reinforcer. An assessment of the mediating factors during development revealed that the lack of tactile stimulation normally received from the mother, but not sustained exposure to the stress hormone corticosterone, contributed to the long-term effects of AR. These findings represent a potential link between early-life social adversity and vulnerability to the development of problems with behavioural inhibition and attention in the presence of appetitive environmental cues.

The principal nucleus of the bed nucleus of the stria terminalis (BNSTp) is an integral component of the mouse accessory olfactory system, and plays a key role in pheromonal processing. In males, this region is not only larger and contains more neurons than in females, but the cells are also larger. The present study examined the relationship between preference for opposite-sex odour and regional volume, cell number and cell size within the BNSTp of both male and female mice. No correlations were found between olfactory preferences and any of the three morphological BNSTp parameters. However, the olfactory preference task results were not congruent with previous research. Therefore, it remains inconclusive whether relationships exist between olfactory preference behaviour and morphology of the BNSTp.

The present study examined social status and adult neurogenesis in the naked mole rat. These animals live in large colonies with a strict reproductive dominance hierarchy; one female and 1-3 males breed, while other members are subordinate and reproductively suppressed. We examined whether social status affects doublecortin (DCX; a marker for immature neurons) immunoreactivity in the dentate gyrus, piriform cortex (PCx), and basolateral amygdala (BLA) by comparing breeders to subordinates. We also examined subordinates removed from their colony and paired with opposite- or same-sex conspecifics for 6 months. Breeders had reduced DCX immunoreactivity in all areas, with BLA effects confined to females. Effects of housing condition were region-specific, with higher PCx DCX immunoreactivity observed in opposite- than same-sex paired subordinates regardless of gonadal status. The opposite pattern was observed in the BLA. Future work will clarify whether findings are attributable to status differences in stress, behavioural plasticity, or life stage.

M5 muscarinic receptors are associated with dopamine neurons of the ventral tegmental area (VTA) and substantia nigra, and provide an important excitatory input to the mesolimbic dopamine system. Here, I studied locomotion induced by systemic morphine (3, 10, 30 mg/kg, i.p.) in M5 knockout mice of the C57Bl/6 (B6) and CD1 x 129SvJ (129) background strains. M5 knockout mice of both strains showed reduced locomotion in response to 30 mg/kg morphine, while only B6 M5 knockout mice showed reduced locomotion in response to 10 mg/kg morphine. In B6 wild-type mice VTA pre-treatment with the non subtype-selective muscarinic receptor antagonist atropine (3 mg per side), but not the non subtype-selective nicotinic receptor antagonist mecamylamine (5 mg per side), reduced locomotion in response to 30 mg/kg (i.p.) morphine to a similar extent as systemic M5 knockout, suggesting that the reduced morphine-induced locomotion in M5 knockout mice was due to the loss of M5 receptors on VTA dopamine neurons. By contrast, in M5 knockout mice, either intra-VTA atropine or mecamylamine alone increased locomotion by almost 3 times relative to saline, and potentiated morphine-induced locomotion. Therefore, in M5 knockout mice, more clearly than in wild-type mice, blockade of either VTA muscarinic or nicotinic receptors activated locomotion. Infusions of morphine (50 ng) into the VTA increased nucleus accumbens dopamine efflux in urethane-anesthetized wild-type mice. Either M5 knockout or pre-treatment with VTA scopolamine (50 ug) in wild-type mice blocked accumbal dopamine efflux in response to VTA morphine. Therefore, M5 receptors are critical for excitation of dopamine neurons by intra-VTA morphine, suggesting that the reduced locomotion produced by systemic morphine in M5 knockout mice was, in part, due to loss of M5-mediated excitation of VTA dopamine neurons by opiates. The locomotion data also show that in the absence of M5 receptors, cholinergic afferents to mesolimbic dopamine neurons are inhibitory. This supports and extends the conclusions from many studies that non-M5 muscarinic receptors inhibit, and M5 receptors excite, dopamine neurons. Loss of M5-mediated excitation results in reduced acute effects of opiates.

M5 muscarinic receptors are associated with dopamine neurons of the ventral tegmental area (VTA) and substantia nigra, and provide an important excitatory input to the mesolimbic dopamine system. Here, I studied locomotion induced by systemic morphine (3, 10, 30 mg/kg, i.p.) in M5 knockout mice of the C57Bl/6 (B6) and CD1 x 129SvJ (129) background strains. M5 knockout mice of both strains showed reduced locomotion in response to 30 mg/kg morphine, while only B6 M5 knockout mice showed reduced locomotion in response to 10 mg/kg morphine. In B6 wild-type mice VTA pre-treatment with the non subtype-selective muscarinic receptor antagonist atropine (3 mg per side), but not the non subtype-selective nicotinic receptor antagonist mecamylamine (5 mg per side), reduced locomotion in response to 30 mg/kg (i.p.) morphine to a similar extent as systemic M5 knockout, suggesting that the reduced morphine-induced locomotion in M5 knockout mice was due to the loss of M5 receptors on VTA dopamine neurons. By contrast, in M5 knockout mice, either intra-VTA atropine or mecamylamine alone increased locomotion by almost 3 times relative to saline, and potentiated morphine-induced locomotion. Therefore, in M5 knockout mice, more clearly than in wild-type mice, blockade of either VTA muscarinic or nicotinic receptors activated locomotion. Infusions of morphine (50 ng) into the VTA increased nucleus accumbens dopamine efflux in urethane-anesthetized wild-type mice. Either M5 knockout or pre-treatment with VTA scopolamine (50 ug) in wild-type mice blocked accumbal dopamine efflux in response to VTA morphine. Therefore, M5 receptors are critical for excitation of dopamine neurons by intra-VTA morphine, suggesting that the reduced locomotion produced by systemic morphine in M5 knockout mice was, in part, due to loss of M5-mediated excitation of VTA dopamine neurons by opiates. The locomotion data also show that in the absence of M5 receptors, cholinergic afferents to mesolimbic dopamine neurons are inhibitory. This supports and extends the conclusions from many studies that non-M5 muscarinic receptors inhibit, and M5 receptors excite, dopamine neurons. Loss of M5-mediated excitation results in reduced acute effects of opiates.

Neuroscientists have long known that brain function is inherently variable. Functional magnetic resonance imaging (fMRI) research often attributes blood oxygen level-dependent (BOLD) signal variance to measurement-related confounds. However, what is typically considered “noise” variance in data may be a vital feature of brain function that reflects development, cognitive adaptability, flexibility, and performance. In the present thesis, we examine how brain signal variability (measured with a modified BOLD time series standard deviation (SDBOLD)) relates to human aging and cognitive performance in a series of studies. In Study 1, we examined brain variability during fixation baseline periods. We found that not only was the SDBOLD pattern robust, its unique age-predictive power was more than five times that of meanBOLD (a common measure of BOLD activity), yet revealed a spatial pattern virtually orthogonal to meanBOLD. Contrary to typical conceptions of age-related neural noise, young adults exhibited greater brain variability overall. In Study 2, we found that younger, faster, and more consistent performers exhibited significantly higher brain variability across three cognitive tasks, and showed greater variability-based regional differentiation compared to older, poorer performing adults. SDBOLD and meanBOLD spatial patterns were again orthogonal across brain measures. Study 3 demonstrated experimental condition-based modulations in SDBOLD. SDBOLD was an effective discriminator between internal (lower variability) and external (higher variability) cognitive demands, particularly in younger, high performing adults. Finally, to gauge the extent that brain variability can be incrementally manipulated within a single cognitive domain, Study 4 examined parametric modulations in SDBOLD on a face processing task in a young-only sample. Results indicated that SDBOLD can be robustly manipulated through experimental control, and that this manipulation linearly follows performance trends across conditions. These studies help establish the age- and performance-relevance of BOLD variability. We thus argue that the precise nature of relations between aging, cognition, and brain function is incompletely characterized by using mean-based brain measures exclusively.

Background: The present study was designed to examine prefrontal cortical processes in anxious children that mediate cognitive regulation in response to emotion-eliciting stimuli, and the changes that occur after anxious children participate in a cognitive behavioral therapy treatment program. Methods: Electroencephalographic activity was recorded from clinically anxious children and typically developing children at pre- and post-treatment sessions. Event-related potential components were recorded while children performed a go/no-go task using facial stimuli depicting angry, calm, and happy expressions. Results: At pre-treatment, anxious children had significantly greater posterior P1 and frontal N2 amplitudes than typically developing children, components associated with attention/arousal and cognitive control, respectively. For the anxious group only, there were no differences in neural activation between face (emotion) types or trial (Go vs. No-go) types. Anxious children who did not improve with treatment showed increased cortical activation within the time window of the P1 at pre-treatment relative to comparison and improver children. From pre- to post-treatment, only anxious children who improved with treatment showed increased cortical activation within the time window of the N2. Conclusions: At pre-treatment, anxious children appeared to show increased cortical activation regardless of the emotional content of the stimuli. Anxious children also showed greater medial-frontal activity regardless of task demands and response accuracy. These findings suggest indiscriminate cortical processes that may underlie the hypervigilant regulatory style seen in clinically anxious individuals. Neural activation patterns following treatment suggest that heightened perceptual vigilance, as represented by increased P1 amplitudes for non-improvers, may have prevented these anxious children from learning the treatment strategies, leading to poorer outcomes. Increased cognitive control, as represented by increased N2 amplitudes for improvers, may have enabled these anxious children to implement treatment strategies more effectively, leading to improved treatment outcomes. Hence, P1 activation may serve as a predictor of treatment outcome, while N2 activation may serve as an indicator of treatment-related outcome. These findings point to the cortical processes that maintain maladaptive functioning versus the cortical processes that underlie successful intervention in clinically anxious children.

The current thesis directly investigated whether changes in the neural correlates of self-regulation (SR) are associated with the effectiveness of treatment for children’s externalizing problems. In order to test this, seventy-one children 8–12 years of age with clinical levels of externalizing behaviour and their parents completed a 12-week cognitive behavioural therapy program (12 sessions) with a parent management training component that was aimed at improving SR. Electroencephalogram (EEG) correlates of SR were evaluated before and after treatment with a go/no-go task requiring inhibitory control on the children. Results showed that event-related potential (ERP) correlates of SR, such as the frontal N2 and frontal P3 event-related potential magnitudes, differed between the clinical sample and a matched comparison group before treatment: the clinical sample had larger N2 magnitudes and smaller frontal P3 magnitudes. Children who showed improvement (45%) with treatment demonstrated a decrease in the magnitude of the N2 in comparison with children who did not improve. For improvers only, source analysis during the time period of the N2 modeled activation decreases in dorsomedial and ventromedial prefrontal cortex as well as the anterior medial temporal lobe. A decrease in N2 magnitudes and corresponding reductions in source activation, in children who improved with treatment, might reflect improved efficiency in the neural mechanisms of SR. These findings may be important steps toward a better identification of neural markers of SR and a better understanding of the mechanisms of treatment efficacy.

There is a paucity of research examining the neurobiological functioning of new mothers who have experienced parental loss during development. The current study investigated the relationship between inconsistent (IC) versus consistent (CC) care and brain activity in regions that comprise a putative neurobiological model of mothering. Mothers were shown positive and negative pictures of their own and an unfamiliar infant. Through repeated measures ANOVAs, it was found that BOLD activity was greater for own infant in the nucleus accumbens (NAC) and amygdala (AMY) and that positive pictures elicited greater BOLD response in the NAC, AMY and anterior cingulate cortex. Interestingly, IC mothers show an even greater response own infant in the NAC and left hypothalamus (HYPO). In the left dorsolateral prefrontal cortex, IC mothers showed greater BOLD response to other infant. Thus, functioning of the maternal circuit, which includes areas strongly implicated in reward, may be altered by early experiences.

Neuroscientists have long known that brain function is inherently variable. Functional magnetic resonance imaging (fMRI) research often attributes blood oxygen level-dependent (BOLD) signal variance to measurement-related confounds. However, what is typically considered “noise” variance in data may be a vital feature of brain function that reflects development, cognitive adaptability, flexibility, and performance. In the present thesis, we examine how brain signal variability (measured with a modified BOLD time series standard deviation (SDBOLD)) relates to human aging and cognitive performance in a series of studies. In Study 1, we examined brain variability during fixation baseline periods. We found that not only was the SDBOLD pattern robust, its unique age-predictive power was more than five times that of meanBOLD (a common measure of BOLD activity), yet revealed a spatial pattern virtually orthogonal to meanBOLD. Contrary to typical conceptions of age-related neural noise, young adults exhibited greater brain variability overall. In Study 2, we found that younger, faster, and more consistent performers exhibited significantly higher brain variability across three cognitive tasks, and showed greater variability-based regional differentiation compared to older, poorer performing adults. SDBOLD and meanBOLD spatial patterns were again orthogonal across brain measures. Study 3 demonstrated experimental condition-based modulations in SDBOLD. SDBOLD was an effective discriminator between internal (lower variability) and external (higher variability) cognitive demands, particularly in younger, high performing adults. Finally, to gauge the extent that brain variability can be incrementally manipulated within a single cognitive domain, Study 4 examined parametric modulations in SDBOLD on a face processing task in a young-only sample. Results indicated that SDBOLD can be robustly manipulated through experimental control, and that this manipulation linearly follows performance trends across conditions. These studies help establish the age- and performance-relevance of BOLD variability. We thus argue that the precise nature of relations between aging, cognition, and brain function is incompletely characterized by using mean-based brain measures exclusively.