Previous research has indicated that the amygdala exerts a modulatory influence on multiple memory systems. Evidence also indicates that emotional state can influence the use of multiple memory systems and that this effect is mediated by the amygdala. Anxiogenic drugs administered during acquisition in a task that can be acquired either through hippocampus-dependent “place” learning or caudate dependent “response” learning, resulted in the predominant use of response learning. It is not known whether inducing anxiety at other behavioral time points will also influence the relative use of multiple memory systems. In experiment 1, male Long-Evans rats were trained to swim from the same start point to an escape platform constantly located in a goal arm. Prior to memory retrieval rats were administered either alpha- two adrenoceptor antagonist RS 79948-197, peripherally (0.03, 0.01, 0.3 mg/kg) or into the basolateral amygdala (0.1 µg), or saline vehicle. Rats treated with RS 79948-197 prior to memory retrieval exhibited caudate-dependent response learning. Previous studies examining the effects of RS 77948-197 on memory were conducted with rats trained in an anxiogenic state and subsequently probed in a drug free state. Experiment 2 examined whether state dependency may account for those results. Animals received peripheral (0.1 mg/kg) or intra-amygdala (0.1 µg) administration of RS 79948-197, prior to both acquisition and memory retrieval. Rats treated with RS 79948- 197 predominantly exhibited response learning. Finally, experiments 3 and 4 examined whether the use of response learning produced by RS79948-197 was due to the impairing effect on hippocampus-dependent memory. Rats that were administered peripheral (0.03 mg/kg) or intra-amygdala (0.1 µg) injections of RS 79948-197 displayed impaired acquisition of the single solution place task relative to control animals. This indicates that place learning was impaired. Over, all the present findings indicate 1) peripheral and intra-amygdala anxiogenic drug administration results in the use of habit memory at both acquisition and retrieval, 2) state dependency does not play a role in the influence of RS 799948-197 on memory system use, 3) the use of response learning produced by peripheral and intra-amygdala injections of RS 79948-197 may result from an impairing effect of hippocampusdependent memory.

archives@tulane.edu / 1 / Katherine Weissmuller

archives@tulane.edu / 1 / Xin Fu

Posttraumatiskt stressyndrom (PTSD) är en sjukdom som är traumarelaterad och svår att få en övergripande bild av då statistiken för antalet drabbade är bristfällig framför allt av ett stort mörkertal. Symtombilden vid denna sjukdom är mycket individuell och de upplevda symtomen är många, vilket skapar en svårighet i att diagnostisera sjukdomen. Vem som helst kan drabbas när som helst under sin livstid och att få en behandling som fungerar är problematisk då ingen exakt bot finns. Under ett trauma påverkas vårt alarmsystem i kroppen för att varna om fara och då har hjärnstrukturen amygdala en övergripande roll. Eftersom amygdala har stor betydelse för vår uppfattning om faror har därför denna studie valt att se om dessa traumatiska händelser orsakar symtomen vid PTSD. Mer specifikt var syftet med denna litteraturstudie att se om förändringar i amygdala och närliggande regioner kan vara bidragande till symtomen som upplevs av individer med PTSD samt vilka neurologiska förändringar som skett/finns i dessa hjärnregioner som kan ha en bidragande faktor till uppkomsten av sjukdomen. Av sex utvalda orginalartiklar kunde det sammantaget konstateras att vissa neurologiska förändringar som amygdala aktivitet och kortikal volym möjligtvis kan ha en koppling till vissa upplevda symtom som bland annat förhöjd vaksamhet och känsloregleringsförmåga. Artikel 1 visade på minskad volym av grå substans i premotorcortex och i främre cingulate cortex (p<0.05)samt att de med PTSD hade svårare att hantera vardagliga utmaningar, var mindre positiva och mer negativa (p<0.0001).Artikel 2 visade på att volymen av grå substans hade korrelationer med svårighetsgraden av PTSD samt symtombilden. Artikel 3 visade att individer med PTSD hade en minskad aktivitet i högra och vänstra amygdala och ventrala striatum (p<0.005). Där emotionellt avtrubbande hade korrelationer med högra ventrala striatum(p<0.05).Artikel 4 såg att de med PTSD hade förändrad cortex, i högra hemisfären var det åttaregioner och i den vänstra sex regionersom antagligen hade samband med totala CAPS poäng. Artikel 5visade att PTSD gruppen hade en ökad respons i högra amygdala vid syn av skrämmande ansikten (p<0.05) samt att högra amygdala aktiviteten hade samband med symtomet förhöjd vaksamhet. Artikel 6 visade att förmågan att reglera känslor var förändrad hos individer med PTSD. Både vid intensifiering av en känsla (amygdala (p<0.04), bakre cingulate cortex (p<0.01), främre cingulate cortex (p<0.04), middle cingulate cortex (p<0.02), vänstra inferior frontal cortex (p<0.04), vänstra putamen (p<0.04), bilaterala inferior parietal loben (p<0.03)) samt vid minskning av känsla (inferior frontal cortex (p<0.01), vänstra putamen (p<0.02), bilaterala inferior parietal loben (p<0.01), insula (p<0.03)).Denna studie kunde alltså inte påvisa tydliga hjärnområden, kopplade till amygdala, vilka hade förändringar som kan ha orsakat uppkomsten av ångestrelaterade besvär vid PTSD. Eftersom hjärnan är mycket komplex och kan bearbeta intryck på väldigt olika sätt kan dessa resultat kanske förklaras med hjälp av att de olika typer av trauman som individerna utsattes för i stor utsträckning påverkade skilda hjärnregioner. Det är alltså därför viktigt att fler studier, med större deltagarantal och likartade traumatiska händelser, fortsätter belysa PTSD symtom och deras koppling mot amygdala och närliggande hjärnregioner för att öka förståelsen för uppkomsten av PTSD. Eftersom kunskapen idag är begränsad vid behandling av PTSD-relaterad symtom behövs dessa frågeställningar klarläggas för att snabbare kunna ställa diagnos och kunna ge tidigbehandling till individer med PTSD. / Post-traumatic stress disorder (PTSD) is a trauma-related disorder that is difficult to get an overall picture of because of lack of statistics regarding affected individuals, most likely due to a large number of unrecorded cases. The symptoms of this disease are very individual and the perceived symptoms are many, which create a difficulty in diagnosing the disease. Anyone can be affected at any time during his or her lifetime, where effective treatment still needs to be developed. During a trauma our alarm systems in the body warns us of danger and then the brain structure amygdala has a central role. Because the amygdala is of great importance for our understanding of dangers, this study set out to examineif these traumatic events cause the symptoms of PTSD. More specifically, the purpose of this study was to examine if changes in the amygdala and nearby regions may contribute to the symptoms experienced by individuals with PTSD, as well as if the neurological changes that occurred in these brain regions may be a contributing factor to the onset of the disease. Of the six selected original articles it could be noted that certain neurological changes, including amygdala activity and cortical volume, could be linked to certain perceived symptoms together with heightened alertness and emotional regulation skills. Article 1 showed reduced volume of gray matter in the premotor cortex and the anterior cingulate cortex (p <0.05), and those individuals with PTSD had more difficulties handling everyday challenges together with less positive attitudes (p <0.0001). Article 2 showed that the volume of gray matter had correlations with the severity of PTSD and symptoms. Article 3 showed that individuals with PTSD had a decreased activity in the right and left amygdala and ventral striatum (p <0.005). There, emotional numbing had correlations with right ventral striatum (p <0.05). Article 4 showed that those with PTSD had altered cortex in the right hemisphere was the eight regions and in the left six regions that probably was associated with total CAPS score. Article 5 indicated that PTSD group had a higher response in the right amygdala at sight of the faces daunting (p <0.05) and the right amygdala activity was associated with elevated symptom vigilance. Article 6 showed that the ability to regulate emotions was altered in individuals with PTSD. Both the intensification of a sense (amygdala (p <0:04), the posterior cingulate cortex (p <0:01), anterior cingulate cortex (p <0:04), middle cingulate cortex (p <0:02), left inferior frontal cortex (p <0:04) left putamen (p <0.04), bilateral inferior parietal lobe (p <0.03)) and the reduction of sensation (the inferior frontal cortex (p <0.01), the left putamen (p<0.02), bilateral inferior parietal lobe (p <0.01 ), insula (p <0:03)). This study could thus not demonstrate distinct brain areas, linked to amygdala, which had changes that may have caused the onset of anxiety-related disorders in PTSD. Since the brain is very complex and can process impressions in very different ways, these results may be explained by the different types of trauma that the individuals were exposed to,which in turn could affect different brain regions. It is thus important that more studies with larger number of participants, and similar traumatic events, continues highlighting PTSD symptoms and their relationship to amygdala and related brain regions to increase understanding of the onset of PTSD. As knowledge today is limited in the treatment of PTSD-related symptoms, these issues must be continuously examined to develop earlier diagnosecriterias and finally propose proper treatments for individuals with PTSD.

Cholecystokinin (CCK) causes panic attacks in humans and increases fear-associated behaviours in rodents by way of CCK-B receptors. The aim of this thesis was to investigate the CCK system behaviourally and anatomically in C57BL6/J mice and to assess the suitability of CCK-IRES-Cre mouse lines for amygdala manipulation. The behavioural results failed to support the startle-activating effect of CCK-4 or the startle-inhibiting effects of CCK-B receptor antagonists, in spite of evidence showing CCK-4 induced activation of c-Fos in the central amygdala. The anatomical results show that CCK-8 expression in the basolateral amygdala (BLA) is comparable to the CCK mRNA expression pattern. These results suggest that viral manipulations in the CCK-IRES-Cre line will induce changes in endogenous CCK systems in the mouse amygdala.

Cholecystokinin (CCK) causes panic attacks in humans and increases fear-associated behaviours in rodents by way of CCK-B receptors. The aim of this thesis was to investigate the CCK system behaviourally and anatomically in C57BL6/J mice and to assess the suitability of CCK-IRES-Cre mouse lines for amygdala manipulation. The behavioural results failed to support the startle-activating effect of CCK-4 or the startle-inhibiting effects of CCK-B receptor antagonists, in spite of evidence showing CCK-4 induced activation of c-Fos in the central amygdala. The anatomical results show that CCK-8 expression in the basolateral amygdala (BLA) is comparable to the CCK mRNA expression pattern. These results suggest that viral manipulations in the CCK-IRES-Cre line will induce changes in endogenous CCK systems in the mouse amygdala.

Neuropeptide B (NPB) and neuropeptide W(NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stress-induced inhibition was attenuated in the CeAL neurons of NPW-/- mice. Moreover, the response of NPW-/- mice to either formalin-induced pain stimuli or a live rat (i. e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW-/- mice in a habituated environment was indistinguishable from that of wildtype mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments.

The way that emotions are processed in the brain has been widely debated. The two leading hypotheses are the cognitive appraisal viewpoint (Lazarus, 1982) and the affective primacy hypothesis (Zajonc, 1980). The former argues that higher cortical structures are needed to evaluate affective stimuli whereas the latter asserts that humans can use information only processed at the subcortical level to influence behavior. The current study tested the presence of this subcortical pathway by using an affective priming task developed by Murphy and Zajonc (1993). Happy and angry faces were presented for 4 ms before the presentation of a neutral stimulus (Chinese Ideograph) that participants were asked to rate based on how much they liked each one. Individuals do not report conscious awareness of primes presented at this suboptimal speed. In a young adult sample, participants rated ideographs preceded by happy primes significantly higher than those preceded by angry primes. Also, the priming effect was only observed in participants who reported a high positive mood. Next, when primes were presented in the left or right hemifield priming was only found in the right hemifield, and was driven by increased ratings for ideographs preceded by happy primes. Patients with epilepsy who have undergone a temporal lobectomy provide a unique opportunity to study emotional processing. In this procedure, not only is the seizure focus (typically the hippocampus) removed, but the amygdala and surrounding areas of the mesial temporal lobe are removed as well. Nine patients post right temporal lobectomy and three patients post left temporal lobectomy completed the study and did not show an effect of priming. However, 21 pre-surgical epilepsy patients were found to give higher liking ratings to ideographs preceded by angry primes as compared to those preceded by happy primes. Overall, these results support the affective primacy hypothesis however they also suggest that patients with temporal lobe dysfunction may process emotional stimuli differentially from controls. In this population, ideographs preceded by angry primes were rated as more liked than those preceded by happy primes. Directions for future studies to clarify the role of the amygdala in emotional processing are discussed. / text

Typescript. Includes appendix with photographs of brain sections. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 86-87).

Synaptic activity can encode and store information in the brain through changes in synaptic strength as well as by control of gene expression. One corollary challenge becomes identifying these activity-dependent regulatory proteins and the underlying mechanisms associated with neuronal functions. By using biochemical, electrophysiological and behavioral approaches in combination with genetic and pharmacological manipulation, I report that LIM domain only 4 (LMO4) is a key regulator of calcium induced calcium release (CICR) and protein tyrosine phosphatase 1B (PTP1B) in the hippocampus and amygdala, respectively. Neuronal ablation of LMO4 in the glutamatergic neurons (LMO4KO) was associated with reduced promoter activity, mRNA, and protein expression of ryanodine receptor 2 (RyR2), suggesting the involvement of LMO4 in the transcriptional regulation. CICR function in LMO4KO mice was severely compromised, reflected by inefficient CICR-mediated electrophysiological responses including afterhyperpolarization, calcium rise from internal stores and glutamate release probability. These changes were accompanied with impaired hippocampal long term potentiation (LTP) and hippocampal-dependent spatial learning ability. LMO4 was also shown to exert a cytoplasmic regulation as an endogenous inhibitor for PTP1B that accounts for tyrosine dephosphorylation of mGluR5 in the amygdala. LMO4KO mice had elevated PTP1B activity and decreased mGluR endocannabinoid signaling, resulting in a profound anxiety phenotype. The potential clinical value of PTP1B/LMO4 is promising, given that intra-amygdala injection of the PTP1B inhibitor Trodusquemine or a PTP1B shRNA alleviated anxiety by restoring eCB signal in LMO4KO mice. Thus this study identified PTP1B as a potential therapeutic target for anxiety, besides the previous findings of its association with obesity and diabetes. Moreover, this PTP1B-mediated anxiety may be a general mechanism during chronic stress. Collectively, these findings identify that LMO4 plays an essential role for non-genomic and genomic regulation in central neurons, providing a mechanism for LMO4 to modulate a wide range of neuronal functions and behavior.