Extensive research in both humans and animals has identified and isolated distinct brain regions essential for different types of memory, supporting the notion of multiple memory systems (MMS). The hippocampus and the striatum are the two systems that have been studied widely and are the focus of our studies. Research involving lesion and pharmacologic manipulations on both memory systems show strong evidence for independence. However, recent evidence suggests that both memory systems can interact as well. Though evidence point also in favor interactions, the mechanisms under which these systems interact are unknown. The experiments in this dissertation primarily focused on understanding how these two systems operate in a normally functioning brain. Two methods were used to investigate our notions: 1) Behavioral experiment measured cellular changes in the levels of phosphorylated CREB (pCREB) in the regions of interest (ROI) 2) Somatic experiments measured changes in the behavior following manipulation of CREB selectively in the ROI. Overall, these experiments demonstrate CREB as a critical neuronal marker that can be used in both interventions. Behavioral intervention experiment showed evidence as a plasticity related changes in the levels of pCREB that suggested both the hippocampus and the striatum might act in a competitive manner, bidirectionally. The somatic intervention experiments used lentiviral (LV) vectors and showed evidence that LV CREB manipulations are suitable for chronic stable expression and can be used to investigate multiple tasks following a single manipulation. LV mutant CREB in the hippocampus impaired memory across two different hippocampus-dependent tasks and demonstrated that CREB is critical for long term memory. Overexpression of wild type CREB in the striatum enhanced striatal memory, but also showed evidence for hippocampus competition and cooperation. Similarly, CREB overexpressed in the hippocampus of young and middle-aged rats demonstrate that CREB might be a rate limiting factor in young, but not in the middle-aged rats. / acase@tulane.edu

Complex cognitive functions require interactions within and between different brain regions by direct anatomical connections or synchronous activation. As such, damage to any region involved in a cognitive process has the potential to affect its function. Impulsivity is a multifaceted construct that, when dysfunctional, contributes to many psychiatric conditions. The striatum has been implicated as an integral part of the neural circuitry of impulsivity. The current work aims to contribute to the understanding of neural dysfunction underlying disorders of impulsivity by examining how striatal damage affects impulsive behavior. It also aims to improve our understanding of whether neural processes involved in impulsivity are also involved in maintaining awareness of one's thoughts and actions. No studies have systematically examined the extent to which damage to the striatum correlates with both changes in impulsive behavior and changes in self-awareness of impulsive personality. In the first experiment, I examined the effects of focal unilateral striatal damage on self-awareness of impulsivity and other personality traits. I predicted that participants with striatal damage (SD) would have less self-awareness of changes in impulsivity and other personality traits after brain damage, as compared to brain damage comparisons (BDC), due to indirect disruption of neural networks responsible for self-referential processing. I tested this prediction using self and collateral versions of the Barratt Impulsiveness scale (BIS) and the Iowa Scales of Personality Change. In partial support of my hypothesis, there were mean differences in self- and collateral-reported impulsivity on the BIS, with self ratings higher than collateral ratings in the SD group. There were no significant differences in the correlations between self- and collateral-reports for current impulsivity, change in impulsivity, or change in other personality traits. In the second experiment, I examined the effects of focal unilateral striatal damage on laboratory measures of impulsivity. I predicted that participants with striatal damage would exhibit lower levels impulsivity than brain damaged comparisons due to structural loss of regions involved in reward/motivation and motor activity. I tested this using impulsive action tasks (Go/NoGo and Stop Signal Tasks) and impulsive choice tasks (Delay and Probability Discounting). In contrast to my hypothesis, SD participants did not exhibit less impulsive action or impulsive choice than BDC participants. In the third experiment, I examined the effects of focal unilateral striatal damage on the integrity of frontostriatal resting state functional connectivity. I predicted that participants with striatal damage would exhibit alterations in functional connectivity between the remaining regions of the frontostriatal network. I tested this by comparing the strength of functional connectivity of the caudate head and ventromedial prefrontal cortex. While my hypothesis was not directly supported, the data showed interesting trends that warrant further exploration. These included stronger caudate-vmPFC resting state functional connectivity on the lesion side, and weaker functional connectivity on the non-lesioned side in striatal participants compared to brain damaged comparisons. Together, these experiments suggest that although unilateral striatal damage does not appear to affect subjective reports or laboratory measures of impulsivity, it may affect the underlying neural networks utilized by the striatum, as evidenced by changes in frontostriatal resting state functional connectivity. This work extends our understanding of the neurobiology of impulsive behavior and self-awareness, at systems level, and may help pave the way for treatments of those with brain injury, such as traumatic brain injury and stroke patients, or psychiatric disorders involving impulsivity.

Relatively little is known about the existence and traits of a possible nucleus accumbens (Acc) region in non-mammals. The current project investigated a likely candidate for such a structure in pigeons, the medioventral (mvMSt) and mediodorsal (mdMSt) parts of avian medial striatum (MSt). The methods employed were threefold: 1) tract-tracing to determine anatomical connections of the MSt; 2) lesion studies to assess MSt's role in a cognitive task (reversal learning); and 3) measuring an immediate-early gene induced protein, ZENK, in striatal regions during courtship behavior in male pigeons. The MSt was found to have many forebrain (amygdala, hippocampus, dorsal thalamus) and midbrain (ventral tegmental area, substantia nigra) connections similar to those of Acc. In addition, differences in connection patterns between mvMSt and mdMSt indicated that mvMSt was comparable to the shell of Acc, while the mdMSt showed characteristics of Acc core. Effects of MSt lesions on pattern discrimination and reversal learning were assessed. Both lesion subjects and controls performed similarly on original discrimination. Furthermore, there were no significant differences in MSt lesioned birds compared to controls. However, there was a tendency for the two groups to make different types of errors. Error patterns indicated that sham-lesioned birds had deficits due to key preference, whereas lesioned birds had fixation on previous reward contingencies (perseverative errors). The performance of the lesioned birds was consistent with Acc lesion effects on reversal learning in mammals. The expression of ZENK in the mvMSt, mdMSt, lateral MSt, and lateral striatum of male birds exposed to either an empty cage or a live female pigeon was quantified. Higher ZENK expression was found in the live pigeon condition for all the striatal structures. However, the degree of difference between live and empty was much higher in the mvMSt and mdMSt than in the other areas. Therefore, mvMSt and mdMSt appear to play a role in anticipatory sexual behaviors, as has been shown in Acc. The anatomical and functional data from the current study indicate that avian mMSt has numerous similarities with mammalian Acc. These findings will contribute to understanding the evolution of mammalian Acc and identifying the functional significance of avian MSt.

Synaptic transmission occurs as a result of either a spontaneous release of presynaptic vesicles or a batch release of presynaptic vesicles driven by action potentials. The physiological consequence of synaptic transmission driven by different patterns and frequencies of presynaptic stimulation has been extensively investigated. However, the physiological nature, mechanism as well as relevance of prolonged presynaptic stimulation have been poorly characterized. In this dissertation, I present three projects in which prolonged stimulation of synaptic transmission in different forms and different brain regions was studied for its effect on synaptic transmission, mechanisms and physiological relevance. In the first project, prolonged electrical stimulation (100 sec) at high frequency induced a deep synaptic depression in acute hippocampal slices, followed by a recovery of synaptic transmission after ~15 min. The deep synaptic depression was attributed to a complete depletion of presynaptic vesicle pools. In the second project, attempts were made to characterize the mechanism of nuclear activation of gene transcription induced by prolonged electrical stimulation (100 sec). Our results demonstrated that reduced inactivation of non-L-type calcium channels failed to provide calcium required for gene transcription, leaving the activation of gene transcription a selective function for L-type calcium channels. In the third project, we sought to study the physiological relevance of enhanced miniature events of inhibitory synapses induced by prolonged chemical stimulation. We showed that prolonged application (2 min) of nicotine to the striatal slice enhanced the frequency of miniature inhibitory currents that was accompanied with a reduction in the amplitude of evoked response. This reduction in the amplitude of evoked responses was ascribed to a compromised action potential invasion of presynaptic terminals possibly due to inactivation of sodium channels resulting from nicotine-induced depolarization. To summarize, prolonged stimulation of presynaptic vesicle release imposes significant influence upon neuron-to-neuron communication, with distinct mechanisms in different brain regions.

In this set of studies the modulation of feedback-based cognitive skill learning was investigated by modulating a probabilistic classification learning (PCL) task to be either emotional or neutral. In the current task, based on the weather prediction task, cue cards were presented on the screen and subjects were asked to predict what they would come across while walking in the woods, in the emotional condition a snake/spider or in the neutral condition a flower/mushroom. Chapter 1 is a review of the animal and human literature of multiple memory systems, amygdala modulation of multiple memory systems, and sleep-dependent procedural memory consolidation.Chapter 2 examined how emotional arousal affected performance, strategy use, and sympathetic nervous system activation in our manipulated PCL task. Subjects highly fearful of the outcomes in the emotional condition showed overall greater skin conductance responses compared to the other groups, as well as retardation in initial cue-outcome acquisition. Individuals who were not fearful of the outcome stimuli used more complex (optimal) strategies after a 24-hr period of memory consolidation relative to the other groups, reflecting greater implicit knowledge of the probabilistic task structure.The purpose of the experiment in Chapter 3 was to examine consolidation-based stabilization and enhancement in an emotional cognitive skill task. There was no effect of sleep on retention or savings on percent correct or strategy use in both the emotional and neutral PCL task. These results conform to recent evidence that probabilistic learning does not show sleep-dependent performance enhancements.Chapter 4 investigated the neural correlates of emotional PCL with functional magnetic resonance imaging. There was greater amygdala and striatal activity in the emotional versus neutral group on Day 1. There was also increased activity in the striatum on Day 2, suggesting an early and lasting bias of emotion on procedural learning. Additionally, there were differences in neural recruitment by subjects using complex versus simple implicit strategies.The findings from this series of experiments have implications for the assessment of psychopathologies that show dysfunction in affective and striatal areas, such as obsessive-compulsive disorder and Tourette's syndrome, and for the development, eventually, of optimal therapies. / Dissertation

<p>The ultimate goal of the nervous systems of all animals is conceptually simple: Manipulate the external environment to maximize one's own survival and reproduction. The myriad means animals employ in pursuit of this goal are astoundingly complex, but constrained by common factors. For example, to ensure survival, all animals must acquire the necessary nutrients to sustain metabolism. Similarly, social interaction of some form is necessary for mating and reproduction. For some animals, the required social interaction goes far beyond that necessary for mating. Humans and many other primates exist in complex social environments, the navigation of which are essential for adaptive behavior. This dissertation is concerned with processes of transforming sensory stimuli regarding both nutritive and social information into motor commands pursuant to the goals of survival and reproduction. Specifically, this dissertation deals with these processes in the rhesus macaque. Using a task in which monkeys make decisions simultaneously weighing outcomes of fruit juices and images of familiar conspecifics, I have examined the neurophysiology of social and nutritive factors as they contribute to choice behavior; with the ultimate goal of understanding how these disparate factors are weighed against each other and combined to produce coherent motor commands that result in adaptive social interactions and the successful procurement of resources. I began my investigation in the lateral intraparietal cortex, a well-studied area of the primate brain implicated in visual attention, oculomotor planning and control, and reward processing. My findings indicate the lateral intraparietal cortex represents social and nutritive reward information in a common neural currency. That is, the summed value of social and nutritive outcomes is proportional to the firing rates of parietal neurons. I continued my investigation in the striatum, a large and functionally diverse subcortical nuclei implicated in motor processing, reward processing and learning. Here I find a different pattern of results. Striatal neurons generally encoded information about either social outcome or juice rewards, but not both, with a medial or lateral bias in the location of social or juice information encoding neurons, respectively. In further contrast to the lateral intraparietal cortex, the firing rates of striatal neurons coding social and nutritive outcome information is heterogeneous and not directly related to the value of the outcome. This dissertation represents a few incremental steps toward understanding how social information and the drive toward social interaction are incorporated with other motivators to influence behavior. Understanding this process is a necessary step for elucidating, treating, and preventing pathologies</p> / Dissertation

Motor cortex, basal ganglia (BG), and thalamus are anatomically arranged in a recurrent loop whose activity is hypothesized to be involved in the selection of motor actions. Direct (dSPN) and indirect (iSPN) striatal projection neurons receive excitatory input from cortex, and are thought to oppositely modulate cortical activity via BG output to thalamus. Here, we test the central tenets of this model in head-restrained mice performing an operant conditioning task using optogenetic manipulation of dSPNs and iSPNs to determine the effects of activity in each pathway on primary motor cortex. We find that dSPN and iSPN activation has bidirectional, robust, and rapid effects on motor cortex that are highly context-dependent, with distinct effects of each pathway during quiescent and active periods. Thus, the effects of activity in each pathway are at times antagonistic and consistent with classic models, whereas in other behavioral contexts the two pathways will work in the same direction or have no effect at all. In a separate but related project, we describe a direct projection from the globus pallidus externa (GP), a central nucleus of the BG, to frontal regions of the cerebral cortex (FC), which is not typically included in models of BG function. Two cell types make up the GP-FC projection, distinguished by their electrophysiological properties, cortical projection patterns and expression of choline acyteltransferase (ChAT), a genetic marker for the neurotransmitter acetylcholine. These cholinergic GP cells receive basal ganglia input and bidirectionally modulate firing in FC of awake mice. Since GP-FC cells receive dopamine sensitive inhibition from iSPNs and dSPNs, this circuit reveals a pathway by which neuropsychiatric pharmaceuticals can act in the BG and yet modulate frontal cortices. Together, these two projects expand our understanding of the complexities of basal ganglia circuitry and its interactions with cortex.

published_or_final_version / Physiology / Master / Master of Philosophy

To survive in a complex changing environment humans frequently need to adapt their behaviour incidentally from normal interactions in the environment without any specific intention to learn. Whilst there is a considerable body of research into incidental learning of sequential information there is still fundamental debate regarding its cognitive basis, the associated neural mechanisms and the way in which it is affected by neurological disease. These issues were explored, in normal participants and neurological patients, using manipulations of the Serial Reaction Task [SRT] in which participants gradually learn a stimulus sequence (usually screen locations) after responding to each item by pressing corresponding response buttons. The first two experiments (chapter 3) demonstrate that the specific metric used to quantify learning and the occurrence of highly salient repeat locations may inflate estimates of learning in tasks with increased motor demands. The next three experiments (chapter 4) examine whether a secondary (not directly behaviourally relevant) information source during the SRT facilitates chunking in memory and overall learning. In a spatial SRT task (specified by horizontal location), additional spatial information (vertical location) enhanced learning but a secondary perceptual property (colour) produced a cost. However, in a perceptual SRT a secondary perceptual property (colour) had no effect. The next study demonstrates that impairments of incidental learning in Parkinson’s disease are partially reduced by administration of l-Dopa. Implications for models of striatal function and studies suggesting implicit learning is impaired by l-Dopa are discussed. Finally, the impact of Deep Brain Stimulation of the GPi is investigated in a population known to have only limited cognitive deficits relating to their illness (dystonia). Despite previous reports of impaired intentional learning in participants with a high genetic risk of Dystonia, there was no evidence for any impairment before or after stimulation. Implications across studies and future research directions are also discussed.

Synaptic transmission occurs as a result of either a spontaneous release of presynaptic vesicles or a batch release of presynaptic vesicles driven by action potentials. The physiological consequence of synaptic transmission driven by different patterns and frequencies of presynaptic stimulation has been extensively investigated. However, the physiological nature, mechanism as well as relevance of prolonged presynaptic stimulation have been poorly characterized. In this dissertation, I present three projects in which prolonged stimulation of synaptic transmission in different forms and different brain regions was studied for its effect on synaptic transmission, mechanisms and physiological relevance. In the first project, prolonged electrical stimulation (100 sec) at high frequency induced a deep synaptic depression in acute hippocampal slices, followed by a recovery of synaptic transmission after ~15 min. The deep synaptic depression was attributed to a complete depletion of presynaptic vesicle pools. In the second project, attempts were made to characterize the mechanism of nuclear activation of gene transcription induced by prolonged electrical stimulation (100 sec). Our results demonstrated that reduced inactivation of non-L-type calcium channels failed to provide calcium required for gene transcription, leaving the activation of gene transcription a selective function for L-type calcium channels. In the third project, we sought to study the physiological relevance of enhanced miniature events of inhibitory synapses induced by prolonged chemical stimulation. We showed that prolonged application (2 min) of nicotine to the striatal slice enhanced the frequency of miniature inhibitory currents that was accompanied with a reduction in the amplitude of evoked response. This reduction in the amplitude of evoked responses was ascribed to a compromised action potential invasion of presynaptic terminals possibly due to inactivation of sodium channels resulting from nicotine-induced depolarization. To summarize, prolonged stimulation of presynaptic vesicle release imposes significant influence upon neuron-to-neuron communication, with distinct mechanisms in different brain regions.