Graduation date: 1994

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

No description available.

The aims of the thesis were to examine i) whether the endogenous opioid system (EOS) is lateralized in human brain areas involved in processing of emotions and pain; ii) whether EOS responses to unilateral brain injury depend on side of lesion, and iii) whether in human alcoholics, this system is involved in molecular adaptations in brain areas relevant for cognitive control of addictive behavior and habit formation. The main findings were that (1) opioid peptides but not opioid receptors and classic neurotransmitters are markedly lateralized in the anterior cingulate cortex involved in processing of  positive and negative emotions and affective component of pain. The region-specific lateralization of neuronal networks expressing opioid peptides may underlie in part lateralization of higher functions in the human brain including emotions and pain. (2) Analysis of the effects of traumatic brain injury (TBI) demonstrated predominant alteration of dynorphin levels in the hippocampus ipsilateral to the injury, while injury to the right hemisphere affected dynorphin levels in the striatum and frontal cortex to a greater extent than that to the left hemisphere. Thus, trauma reveals a lateralization in the mechanisms mediating the response of dynorphin expressing neuronal networks in the brain. These networks may differentially mediate effects of left or right brain injury on lateralized brain functions. (3) In human alcoholics, the enkephalin and dynorphin systems were found to be downregulated in the caudate nucleus and / or putamen that may underlie in part changes in goal directed behavior and formation of a compulsive habit in alcoholics. In contrast to downregulation in these areas, PDYN mRNA and dynorphins in dorsolateral prefrontal cortex, k-opioid receptor mRNA in orbitofrontal cortex, and dynorphins in hippocampus were upregulated in alcoholics. Activation of the k-opioid receptor by upregulated dynorphins may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control. We conclude that the EOS exhibits region-specific lateralization in human brain and brain-area specific lateralized response after unilateral TBI in mice; and that the EOS is involved in adaptive processes associated with specific aspects of alcohol dependence.

Organisms must continuously navigate complex environments, balancing the drive to seek rewards with the need to avoid potential threats. This tradeoff between approach and avoidance behaviors, known as approach-avoidance conflict, is a critical determinant of survival. The medial prefrontal cortex (mPFC) plays a key role in regulating these behaviors, with the ventromedial (vmPFC) and dorsomedial components thought to suppress and promote, respectively, behavioral responses to threats. Within the vmPFC, neural populations expressing the opioid peptide dynorphin (Dyn) and its receptor, the kappa opioid receptor (KOR), have been implicated in stress responses. However, the specific role of the vmPFC Dyn system in encoding threat-related information and shaping behavioral responses remains largely unexplored. To address this, we employed a multi-faceted approach, utilizing fiber photometry, calcium imaging, shRNA-mediated knockdown, and DREADD-mediated inhibition to investigate the vmPFC Dyn system in various threat-related paradigms. These included the platform-mediated avoidance (PMA) task, which assesses approach-avoidance conflict; the repeated looming disk test, a pain-free model of innate fear suppression; and standard fear conditioning, a well-established paradigm for studying learned fear responses. Our findings reveal that while the vmPFC Dyn system is not differentially regulated under non-threatening baseline conditions, it is actively recruited upon threat exposure. Fiber photometry recordings during the PMA task showed that vmPFC Dyn neurons bidirectionally signal features related to approach and avoidance behaviors in the presence of threat. Furthermore, shRNA-mediated downregulation of Dyn in the vmPFC led to enhanced avoidance in the repeated looming disk test, indicating that Dyn is necessary for suppressing avoidance in this context. Calcium imaging of the pan-neuronal vmPFC population in conjunction with Dyn knockdown revealed that loss of Dyn impairs cortical activity, as evidenced by reduced synchrony and decreased performance of a logistic regression decoder. These findings suggest that Dyn plays a critical role in shaping the activity of vmPFC neurons during threat processing. Taken together, our results highlight a specific role for the vmPFC Dyn system in toggling threat-driven behavioral responses, particularly in the context of approach-avoidance conflict. By demonstrating how Dyn shapes both behavior and neural activity in the vmPFC during threat exposure, this study provides novel insights into an understudied area of opioidergic circuitry. Moreover, our findings contribute to a deeper understanding of how distinct cell types within the vmPFC encode threat-related features to promote or suppress avoidance behaviors, shedding light on the neural mechanisms underlying adaptive responses to environmental challenges.

Les dynorphines sont des neuropeptides importants avec un rôle central dans la nociception et l’atténuation de la douleur. De nombreux mécanismes régulent les concentrations de dynorphine endogènes, y compris la protéolyse. Les Proprotéines convertases (PC) sont largement exprimées dans le système nerveux central et clivent spécifiquement le C-terminale de couple acides aminés basiques, ou un résidu basique unique. Le contrôle protéolytique des concentrations endogènes de Big Dynorphine (BDyn) et dynorphine A (Dyn A) a un effet important sur la perception de la douleur et le rôle de PC reste à être déterminée. L'objectif de cette étude était de décrypter le rôle de PC1 et PC2 dans le contrôle protéolytique de BDyn et Dyn A avec l'aide de fractions cellulaires de la moelle épinière de type sauvage (WT), PC1 -/+ et PC2 -/+ de souris et par la spectrométrie de masse. Nos résultats démontrent clairement que PC1 et PC2 sont impliquées dans la protéolyse de BDyn et Dyn A avec un rôle plus significatif pour PC1. Le traitement en C-terminal de BDyn génère des fragments peptidiques spécifiques incluant dynorphine 1-19, dynorphine 1-13, dynorphine 1-11 et dynorphine 1-7 et Dyn A génère les fragments dynorphine 1-13, dynorphine 1-11 et dynorphine 1-7. Ils sont tous des fragments de peptides associés à PC1 ou PC2. En plus, la protéolyse de BDyn conduit à la formation de Dyn A et Leu-Enk, deux peptides opioïdes importants. La vitesse de formation des deux est réduite de manière significative dans les fractions cellulaires de la moelle épinière de souris mutantes. En conséquence, l'inhibition même partielle de PC1 ou PC2 peut altérer le système opioïde endogène. / Dynorphins are important neuropeptides with a central role in nociception and pain alleviation. Many mechanisms regulate endogenous dynorphin concentrations, including proteolysis. Proprotein convertases (PCs) are widely expressed in the central nervous system and specifically cleave at C-terminal of either a pair of basic amino acids, or a single basic residue. The proteolysis control of endogenous Big Dynorphin (BDyn) and Dynorphin A (Dyn A) levels has a profound impact on pain perception and the role of PCs remain unclear. The objective of this study was to decipher the role of PC1 and PC2 in the proteolysis control of BDyn and Dyn A levels using cellular fractions of spinal cords from wild type (WT), PC1-/+ and PC2-/+ animals and mass spectrometry. Our results clearly demonstrate that both PC1 and PC2 are involved in the proteolysis regulation of BDyn and Dyn A with a more important role for PC1. C-terminal processing of BDyn generates specific peptide fragments Dynorphin 1-19, Dynorphin 1-13, Dynorphin 1-11 and Dynorphin 1-7 and C-terminal processing of Dyn A generates Dynorphin 1-13, Dynorphin 1-11 and Dynorphin 1-7, all these peptide fragments are associated with PC1 or PC2 processing. Moreover, proteolysis of BDyn leads to the formation of Dyn A and Leu-Enk, two important opioid peptides. The rate of formation of both is significantly reduced in cellular fractions of spinal cord mutant mice. As a consequence, even partial inhibition of PC1 or PC2 may impair the endogenous opioid system.