Browsing by Subject "Hippocampus"
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Item Open Access A Peptide Uncoupling BDNF Receptor TrkB from Phospholipase Cγ1 Prevents Epilepsy Induced by Status Epilepticus.(Neuron, 2015-11-04) Gu, Bin; Huang, Yang Zhong; He, Xiao-Ping; Joshi, Rasesh B; Jang, Wonjo; McNamara, James OThe BDNF receptor tyrosine kinase, TrkB, underlies nervous system function in both health and disease. Excessive activation of TrkB caused by status epilepticus promotes development of temporal lobe epilepsy (TLE), revealing TrkB as a therapeutic target for prevention of TLE. To circumvent undesirable consequences of global inhibition of TrkB signaling, we implemented a novel strategy aimed at selective inhibition of the TrkB-activated signaling pathway responsible for TLE. Our studies of a mouse model reveal that phospholipase Cγ1 (PLCγ1) is the dominant signaling effector by which excessive activation of TrkB promotes epilepsy. We designed a novel peptide (pY816) that uncouples TrkB from PLCγ1. Treatment with pY816 following status epilepticus inhibited TLE and prevented anxiety-like disorder yet preserved neuroprotective effects of endogenous TrkB signaling. We provide proof-of-concept evidence for a novel strategy targeting receptor tyrosine signaling and identify a therapeutic with promise for prevention of TLE caused by status epilepticus in humans.Item Open Access Age-related effects on the neural correlates of autobiographical memory retrieval.(Neurobiol Aging, 2012-07) St Jacques, Peggy L; Rubin, David C; Cabeza, RobertoOlder adults recall less episodically rich autobiographical memories (AM), however, the neural basis of this effect is not clear. Using functional MRI, we examined the effects of age during search and elaboration phases of AM retrieval. Our results suggest that the age-related attenuation in the episodic richness of AMs is associated with difficulty in the strategic retrieval processes underlying recovery of information during elaboration. First, age effects on AM activity were more pronounced during elaboration than search, with older adults showing less sustained recruitment of the hippocampus and ventrolateral prefrontal cortex (VLPFC) for less episodically rich AMs. Second, there was an age-related reduction in the modulation of top-down coupling of the VLPFC on the hippocampus for episodically rich AMs. In sum, the present study shows that changes in the sustained response and coupling of the hippocampus and prefrontal cortex (PFC) underlie age-related reductions in episodic richness of the personal past.Item Open Access Amygdala volume changes in posttraumatic stress disorder in a large case-controlled veterans group.(Arch Gen Psychiatry, 2012-11) Morey, Rajendra A; Gold, Andrea L; LaBar, Kevin S; Beall, Shannon K; Brown, Vanessa M; Haswell, Courtney C; Nasser, Jessica D; Wagner, H Ryan; McCarthy, Gregory; Mid-Atlantic MIRECC WorkgroupCONTEXT: Smaller hippocampal volumes are well established in posttraumatic stress disorder (PTSD), but the relatively few studies of amygdala volume in PTSD have produced equivocal results. OBJECTIVE: To assess a large cohort of recent military veterans with PTSD and trauma-exposed control subjects, with sufficient power to perform a definitive assessment of the effect of PTSD on volumetric changes in the amygdala and hippocampus and of the contribution of illness duration, trauma load, and depressive symptoms. DESIGN: Case-controlled design with structural magnetic resonance imaging and clinical diagnostic assessments. We controlled statistically for the important potential confounds of alcohol use, depression, and medication use. SETTING: Durham Veterans Affairs Medical Center, which is located in proximity to major military bases. PATIENTS: Ambulatory patients (n = 200) recruited from a registry of military service members and veterans serving after September 11, 2001, including a group with current PTSD (n = 99) and a trauma-exposed comparison group without PTSD (n = 101). MAIN OUTCOME MEASURE: Amygdala and hippocampal volumes computed from automated segmentation of high-resolution structural 3-T magnetic resonance imaging. RESULTS: Smaller volume was demonstrated in the PTSD group compared with the non-PTSD group for the left amygdala (P = .002), right amygdala (P = .01), and left hippocampus (P = .02) but not for the right hippocampus (P = .25). Amygdala volumes were not associated with PTSD chronicity, trauma load, or severity of depressive symptoms. CONCLUSIONS: These results provide clear evidence of an association between a smaller amygdala volume and PTSD. The lack of correlation between trauma load or illness chronicity and amygdala volume suggests that a smaller amygdala represents a vulnerability to developing PTSD or the lack of a dose-response relationship with amygdala volume. Our results may trigger a renewed impetus for investigating structural differences in the amygdala, its genetic determinants, its environmental modulators, and the possibility that it reflects an intrinsic vulnerability to PTSD.Item Open Access Amygdala, Hippocampus, and Ventral Medial Prefrontal Cortex Volumes Differ in Maltreated Youth with and without Chronic Posttraumatic Stress Disorder.(Neuropsychopharmacology, 2016-02) Morey, Rajendra A; Haswell, Courtney C; Hooper, Stephen R; De Bellis, Michael DPosttraumatic stress disorder (PTSD) is considered a disorder of recovery where individuals fail to learn and retain extinction of the traumatic fear response. In maltreated youth, PTSD is common, chronic, and associated with comorbidity. Studies of extinction-related structural volumes (amygdala, hippocampus, anterior cingulate cortex (ACC), and ventral medial prefrontal cortex (vmPFC)) and this stress diathesis, in maltreated youth were not previously investigated. In this cross-sectional study, neuroanatomical volumes associated with extinction in maltreated youth with PTSD (N=31), without PTSD (N=32), and in non-maltreated healthy volunteers (n=57) were examined using magnetic resonance imaging. Groups were sociodemographically similar. Participants underwent extensive assessments for strict inclusion/exclusion criteria and DSM-IV disorders. Maltreated youth with PTSD demonstrated decreased right vmPFC volumes compared with both maltreated youth without PTSD and non-maltreated controls. Maltreated youth without PTSD demonstrated larger left amygdala and right hippocampal volumes compared with maltreated youth with PTSD and non-maltreated control youth. PTSD symptoms inversely correlated with right and left hippocampal and left amygdala volumes. Confirmatory masked voxel base morphometry analyses demonstrated greater medial orbitofrontal cortex gray matter intensity in controls than maltreated youth with PTSD. Volumetric results were not influenced by psychopathology or maltreatment variables. We identified volumetric differences in extinction-related structures between maltreated youth with PTSD from those without PTSD. Alterations of the vmPFC may be one mechanism that mediates the pathway from PTSD to comorbidity. Further longitudinal work is needed to determine neurobiological factors related to chronic and persistent PTSD, and to PTSD resilience despite maltreatment.Item Open Access Brain activity during episodic retrieval of autobiographical and laboratory events: an fMRI study using a novel photo paradigm.(J Cogn Neurosci, 2004-11) Cabeza, Roberto; Prince, Steve E; Daselaar, Sander M; Greenberg, Daniel L; Budde, Matthew; Dolcos, Florin; LaBar, Kevin S; Rubin, David CFunctional neuroimaging studies of episodic memory retrieval generally measure brain activity while participants remember items encountered in the laboratory ("controlled laboratory condition") or events from their own life ("open autobiographical condition"). Differences in activation between these conditions may reflect differences in retrieval processes, memory remoteness, emotional content, retrieval success, self-referential processing, visual/spatial memory, and recollection. To clarify the nature of these differences, a functional MRI study was conducted using a novel "photo paradigm," which allows greater control over the autobiographical condition, including a measure of retrieval accuracy. Undergraduate students took photos in specified campus locations ("controlled autobiographical condition"), viewed in the laboratory similar photos taken by other participants (controlled laboratory condition), and were then scanned while recognizing the two kinds of photos. Both conditions activated a common episodic memory network that included medial temporal and prefrontal regions. Compared with the controlled laboratory condition, the controlled autobiographical condition elicited greater activity in regions associated with self-referential processing (medial prefrontal cortex), visual/spatial memory (visual and parahippocampal regions), and recollection (hippocampus). The photo paradigm provides a way of investigating the functional neuroanatomy of real-life episodic memory under rigorous experimental control.Item Open Access Calcium-based plasticity model explains sensitivity of synaptic changes to spike pattern, rate, and dendritic location.(Proceedings of the National Academy of Sciences of the United States of America, 2012-03) Graupner, Michael; Brunel, NicolasMultiple stimulation protocols have been found to be effective in changing synaptic efficacy by inducing long-term potentiation or depression. In many of those protocols, increases in postsynaptic calcium concentration have been shown to play a crucial role. However, it is still unclear whether and how the dynamics of the postsynaptic calcium alone determine the outcome of synaptic plasticity. Here, we propose a calcium-based model of a synapse in which potentiation and depression are activated above calcium thresholds. We show that this model gives rise to a large diversity of spike timing-dependent plasticity curves, most of which have been observed experimentally in different systems. It accounts quantitatively for plasticity outcomes evoked by protocols involving patterns with variable spike timing and firing rate in hippocampus and neocortex. Furthermore, it allows us to predict that differences in plasticity outcomes in different studies are due to differences in parameters defining the calcium dynamics. The model provides a mechanistic understanding of how various stimulation protocols provoke specific synaptic changes through the dynamics of calcium concentration and thresholds implementing in simplified fashion protein signaling cascades, leading to long-term potentiation and long-term depression. The combination of biophysical realism and analytical tractability makes it the ideal candidate to study plasticity at the synapse, neuron, and network levels.Item Open Access Capturing characteristic features in the human cortical gray matter and hippocampus in vivo using submillimeter diffusion MRI(2022) Ma, YixinAlzheimer's disease (AD) accounts for 60%-80% of dementia. AD patients start by having mild memory, language, and thinking difficulties, then gradually lose more critical abilities, such as dressing, bathing, or walking. AD not only degrades patients’ life quality but also burdens caregivers and the health system. Specifically, there are 6.5 million AD cases in the U.S. today, and the annual health costs for 2022 are estimated to be $321 billion. AD diagnosis has been evolving in the past 30 years. The criteria established in 1984 recommended that AD cannot be identified until a post-mortem neuropathological test is performed. Recently, more biomarkers have gradually been discovered, such as brain atrophy, Positron Emission Tomography (PET) measures of glucose hypometabolism, and cerebrospinal fluid (CSF) and PET measures of pathological amyloid-beta and tau. However, these biomarkers lack the specificity to probe the damage in the neuronal microstructure that directly causes the disease, and they only provide late diagnoses when the AD progression is no longer reversible. Since the neuronal damages are believed to begin 20 years or more before symptoms start, biomarkers that can detect abnormalities in the neuronal microstructure would enable the diagnosis of AD at the very early stage of neurodegeneration, years before the onset of symptoms, and they could thus potentially enable better treatment outcomes since neuronal damage at the early stage could be reversible.Diffusion tensor imaging (DTI) is a magnetic resonance imaging technique that can noninvasively probe the microstructure of the human brain in vivo. Some regions in the cortical gray matter and hippocampus are known to experience early neurodegeneration in AD, and changes in DTI metrics in these regions could reflect the early stage of AD. However, the cortex is folded and is made of different cortical layers and cortical regions and the hippocampus is made of different subfields that have distinct neuronal populations with a specific microstructure. Additionally, neurodegeneration does not necessarily occur at the same time across different cortical depths or regions in the cortex or across different subfields in the hippocampus. As such, the development of early diagnostic biomarkers would require the ability to probe the neuronal microstructure at specific cortical depths and in specific cortical regions and hippocampal subfields in vivo. However, doing so with DTI has been challenging because the average cortical thickness is only 2.5 mm and the average hippocampal volume is only 2.84 mL. Therefore, a high-resolution DTI acquisition within a reasonable scan time is needed. In this dissertation, we first aim to develop DTI acquisition and reconstruction methodologies to acquire high-resolution (0.9-mm to 1.0-mm isotropic) whole-brain DTI images. Specifically, we used an efficient multi-band multi-shot echo-planar imaging sequence and a multi-band multiplexed sensitivity-encoding reconstruction. Furthermore, we aim to develop a data analysis pipeline that can quantitatively probe the microstructure and capture characteristic features: 1) in the cortex by performing a column-based cortical depth analysis of the diffusion anisotropy and radiality; and 2) in the hippocampus by investigating intra-hippocampal fiber tracts and connectomes, with the long-term goal of enabling the early diagnosis of AD. In the cortex, a column-based cortical depth analysis that samples the fractional anisotropy (FA) and radiality index (RI) along radially oriented cortical columns was performed to quantitatively analyze the FA and RI dependence on the cortical depth, cortical region, cortical curvature, and cortical thickness across the whole brain. We first studied young healthy subjects to optimize the data acquisition and analysis pipeline and to investigate the consistency of the results. The results showed characteristic FA and RI vs. cortical depth profiles, with an FA local maximum and minimum (or two inflection points) and a single RI maximum at intermediate cortical depths in most cortical regions, except for the postcentral gyrus where no FA peaks and a lower RI were observed. These results were consistent between repeated scans from the same subjects and across different subjects. They were also dependent on the cortical curvature and cortical thickness in that the characteristic FA and RI peaks were more pronounced i) at the banks than at the crown of gyri or at the fundus of sulci and ii) as the cortical thickness increases. We then performed a preliminary clinical study in a small cohort of AD patients and age-matched healthy controls (HC) to further examine if this methodology could be applied to detect differences in the FA and RI vs. cortical depth profiles between the AD and HC groups. The FA and RI at each cortical depth and in different regions of interest (ROIs) were sampled and compared between these two groups to look for any significant differences. Additionally, based on the results from the young healthy subjects, we minimized the dependence of these DTI metrics (FA and RI) on structural metrics such as cortical thickness and cortical curvature. The results showed significant differences (p < 0.05) in the FA and RI profiles between the AD and HC groups for specific cortical depths, curvature subsets, and ROIs. To generate intra-hippocampal fiber tracts and connectomes, the hippocampus of all subjects was registered to a common template and deterministic fiber tracking was performed. The fiber orientations across hippocampal subfields were investigated, and the connectivity among subfields was quantified. The results showed characteristic fiber orientations in different hippocampal subfields that were generally consistent between repeated scans and across all subjects: right/left in the middle of the CA4/dentate gyrus subfield and the inferior part of the subiculum; anterior/posterior in CA2/CA3; superior/inferior in the medial and inferior parts of the molecular layer and subiculum. These in vivo fiber orientations aligned with those obtained from an ex vivo specimen scanned over 21 hours at a 0.2-mm isotropic resolution. However, the ex vivo scan delineated the C-shaped molecular layer, which was not shown in the in vivo scans. The in vivo connectomes were generally consistent between repeated scans and across all subjects. The in vivo and ex vivo connectomes both showed more connectivity within the head than within the body of the hippocampus; however, the in vivo and ex vivo connectivity ranking across pairs of subfields was not exactly the same, which could be explained by altered diffusion properties in the ex vivo sample due to fixation or by the higher resolution in the ex vivo scan. In conclusion, the proposed high-resolution whole-brain DTI acquisition, column-based cortical depth analysis of the diffusion anisotropy and radiality, and intra-hippocampal fiber tracking captured characteristic features of FA and RI vs. cortical depth profiles in the cortex and characteristic fiber orientations and connectivity strengths across different subfields of the hippocampus, which were consistent between repeated scans from the same subjects and across different subjects. In addition, the cortical analysis applied in a preliminary clinical study of AD patients vs. HC showed significant differences in the FA and RI profiles between these two groups, showing the potential of this methodology to generate biomarkers for the early diagnosis of AD.
Item Open Access Characteristics of sequential activity in networks with temporally asymmetric Hebbian learning.(Proceedings of the National Academy of Sciences of the United States of America, 2020-11-11) Gillett, Maxwell; Pereira, Ulises; Brunel, NicolasSequential activity has been observed in multiple neuronal circuits across species, neural structures, and behaviors. It has been hypothesized that sequences could arise from learning processes. However, it is still unclear whether biologically plausible synaptic plasticity rules can organize neuronal activity to form sequences whose statistics match experimental observations. Here, we investigate temporally asymmetric Hebbian rules in sparsely connected recurrent rate networks and develop a theory of the transient sequential activity observed after learning. These rules transform a sequence of random input patterns into synaptic weight updates. After learning, recalled sequential activity is reflected in the transient correlation of network activity with each of the stored input patterns. Using mean-field theory, we derive a low-dimensional description of the network dynamics and compute the storage capacity of these networks. Multiple temporal characteristics of the recalled sequential activity are consistent with experimental observations. We find that the degree of sparseness of the recalled sequences can be controlled by nonlinearities in the learning rule. Furthermore, sequences maintain robust decoding, but display highly labile dynamics, when synaptic connectivity is continuously modified due to noise or storage of other patterns, similar to recent observations in hippocampus and parietal cortex. Finally, we demonstrate that our results also hold in recurrent networks of spiking neurons with separate excitatory and inhibitory populations.Item Unknown Co-activation of the amygdala, hippocampus and inferior frontal gyrus during autobiographical memory retrieval.(Neuropsychologia, 2005) Greenberg, Daniel L; Rice, Heather J; Cooper, Julie J; Cabeza, Roberto; Rubin, David C; Labar, Kevin SFunctional MRI was used to investigate the role of medial temporal lobe and inferior frontal lobe regions in autobiographical recall. Prior to scanning, participants generated cue words for 50 autobiographical memories and rated their phenomenological properties using our autobiographical memory questionnaire (AMQ). During scanning, the cue words were presented and participants pressed a button when they retrieved the associated memory. The autobiographical retrieval task was interleaved in an event-related design with a semantic retrieval task (category generation). Region-of-interest analyses showed greater activation of the amygdala, hippocampus, and right inferior frontal gyrus during autobiographical retrieval relative to semantic retrieval. In addition, the left inferior frontal gyrus showed a more prolonged duration of activation in the semantic retrieval condition. A targeted correlational analysis revealed pronounced functional connectivity among the amygdala, hippocampus, and right inferior frontal gyrus during autobiographical retrieval but not during semantic retrieval. These results support theories of autobiographical memory that hypothesize co-activation of frontotemporal areas during recollection of episodes from the personal past.Item Unknown Contributions of Dorsal/Ventral Hippocampus and Dorsolateral/Dorsomedial Striatum to Interval Timing(2016) Yin, Bin YinHumans and animals have remarkable capabilities in keeping time and using time as a guide to orient their learning and decision making. Psychophysical models of timing and time perception have been proposed for decades and have received behavioral, anatomical and pharmacological data support. However, despite numerous studies that aimed at delineating the neural underpinnings of interval timing, a complete picture of the neurobiological network of timing in the seconds-to-minutes range remains elusive. Based on classical interval timing protocols and proposing a Timing, Immersive Memory and Emotional Regulation (TIMER) test battery, the author investigates the contributions of the dorsal and ventral hippocampus as well as the dorsolateral and the dorsomedial striatum to interval timing by comparing timing performances in mice after they received cytotoxic lesions in the corresponding brain regions. On the other hand, a timing-based theoretical framework for the emergence of conscious experience that is closely related to the function of the claustrum is proposed so as to serve both biological guidance and the research and evolution of “strong” artificial intelligence. Finally, a new “Double Saturation Model of Interval Timing” that integrates the direct- and indirect- pathways of striatum is proposed to explain the set of empirical findings.
Item Unknown Deferoxamine regulates neuroinflammation and iron homeostasis in a mouse model of postoperative cognitive dysfunction.(J Neuroinflammation, 2016-10-12) Li, Yuping; Pan, Ke; Chen, Lin; Ning, Jiao-Lin; Li, Xiaojun; Yang, Ting; Terrando, Niccolò; Gu, Jianteng; Tao, GuocaiBACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after surgery, especially amongst elderly patients. Neuroinflammation and iron homeostasis are key hallmarks of several neurological disorders. In this study, we investigated the role of deferoxamine (DFO), a clinically used iron chelator, in a mouse model of surgery-induced cognitive dysfunction and assessed its neuroprotective effects on neuroinflammation, oxidative stress, and memory function. METHODS: A model of laparotomy under general anesthesia and analgesia was used to study POCD. Twelve to 14 months C57BL/6J male mice were treated with DFO, and changes in iron signaling, microglia activity, oxidative stress, inflammatory cytokines, and neurotrophic factors were assessed in the hippocampus on postoperative days 3, 7, and 14. Memory function was evaluated using fear conditioning and Morris water maze tests. BV2 microglia cells were used to test the anti-inflammatory and neuroprotective effects of DFO. RESULTS: Peripheral surgical trauma triggered changes in hippocampal iron homeostasis including ferric iron deposition, increase in hepcidin and divalent metal transporter-1, reduction in ferroportin and ferritin, and oxidative stress. Microglia activation, inflammatory cytokines, brain-derived neurotropic factor impairments, and cognitive dysfunction were found up to day 14 after surgery. Treatment with DFO significantly reduced neuroinflammation and improved cognitive decline by modulating p38 MAPK signaling, reactive oxygen species, and pro-inflammatory cytokines release. CONCLUSIONS: Iron imbalance represents a novel mechanism underlying surgery-induced neuroinflammation and cognitive decline. DFO treatment regulates neuroinflammation and microglia activity after surgery.Item Unknown Demographic, maltreatment, and neurobiological correlates of PTSD symptoms in children and adolescents.(J Pediatr Psychol, 2010-06) De Bellis, Michael D; Hooper, Stephen R; Woolley, Donald P; Shenk, Chad EOBJECTIVE: To examine the relationships of demographic, maltreatment, neurostructural and neuropsychological measures with total posttraumatic stress disorder (PTSD) symptoms. METHODS: Participants included 216 children with maltreatment histories (N = 49), maltreatment and PTSD (N = 49), or no maltreatment (N = 118). Participants received diagnostic interviews, brain imaging, and neuropsychological evaluations. RESULTS: We examined a hierarchical regression model comprised of independent variables including demographics, trauma and maltreatment-related variables, and hippocampal volumes and neuropsychological measures to model PTSD symptoms. Important independent contributors to this model were SES, and General Maltreatment and Sexual Abuse Factors. Although hippocampal volumes were not significant, Visual Memory was a significant contributor to this model. CONCLUSIONS: Similar to adult PTSD, pediatric PTSD symptoms are associated with lower Visual Memory performance. It is an important correlate of PTSD beyond established predictors of PTSD symptoms. These results support models of developmental traumatology and suggest that treatments which enhance visual memory may decrease symptoms of PTSD.Item Unknown Dietary Choline, Inflammation, and Neuroprotection Across the Lifespan(2020) Maurer, SaraThe cholinergic system is intricately linked with hippocampal memory. As well, choline is anti-inflammatory in the brain and periphery (Terrando et al., 2011; Rivera et al., 1998). However, few have analyzed the anti-inflammatory properties of choline as an alternate means by which cholinergic manipulations affect hippocampal memory throughout the lifespan. The first aim of this dissertation work sought to determine if dietary choline supplementation protects against the deleterious effects of air pollution in the developing brain. Pregnant mice were given a high-choline diet (approximately 4.5x the choline chloride in the control diet) or a synthetic control diet. As well, dams were exposed to a series of diesel particulate (DEP) or saline vehicle sessions throughout pregnancy. Mice were sacrificed and tissues were collected on embryonic day 18. The activation state of microglia, identified by quantifying morphology using Iba1+ immunohistochemical staining, was examined in the dentate gyrus of the hippocampus (DG), the paraventricular nucleus (PVN) of the hypothalamus, the basolateral amygdala (AMY), and the parietal cortex (PCX). As expected, we found that DEP led to increased microglial activation in the fetal DG in males. Choline supplementation partially prevented this increase in activation. Interestingly, these effects were region-specific: the opposite pattern is seen in the PVN, and no significant diesel effect was seen in the AMY and PCX. These findings suggest that prenatal choline supplementation throughout pregnancy may protect the fetal hippocampus against the neuroinflammation associated with air pollution. To analyze whether the acute effects of dietary choline seen prenatally also occur in adulthood, adult dietary choline supplementation alongside the tibial fracture model of post-operative cognitive dysfunction (POCD) was used. POCD occurs when increased neuroinflammation due to peripheral surgery leads to impairments in cognition. Differences were found in almost hippocampal-dependent behavior, astrocytic activation, and cell proliferation. Differences were time point-specific. In the hippocampus, astrocytic activation, cell proliferation, and hilar granule cells all increased 1 day after surgery, and these increases were blunted by dietary choline. An increase in hippocampal young neurons was found 2 weeks after surgery. However, both were blunted by choline supplementation. At both time points assessed, tibial fracture impaired novel object recognition performance, and dietary choline rescued these impairments. As well, dietary choline supplementation did not mitigate the increase in anxiety-related behavior – specifically implicating hippocampal actions of the nutrient. Because the hippocampal-dependent memory impairment and rescue is not time point-specific, but the neural effects of tibial fracture are each specific to a certain timepoint, the mechanisms of behavior are likely different at each time point. Building upon aim 2, aim 3 explores if perinatal choline supplementation can act via “programming” of the neuroimmune system in development to prevent POCD in adulthood. Perinatal choline supplementation prevented POCD and neuroinflammation due to peripheral surgery, but did not protect against increases in young neurons or hilar neurons. Perinatal choline nutrition, in addition to its already-known neuroprotection, is additionally protective against POCD and its associated neuroinflammation in adulthood. Taken together, this body of work concludes that dietary choline supplementation at various administration dates is protective in neuroinflammatory models in behavior and brain.
Item Unknown Dosimetric analysis of the alopecia preventing effect of hippocampus sparing whole brain radiation therapy.(Radiat Oncol, 2015-11-26) Mahadevan, Anand; Sampson, Carrie; LaRosa, Salvatore; Floyd, Scott R; Wong, Eric T; Uhlmann, Erik J; Sengupta, Soma; Kasper, Ekkehard MBACKGROUND: Whole brain radiation therapy (WBRT) is widely used for the treatment of brain metastases. Cognitive decline and alopecia are recognized adverse effects of WBRT. Recently hippocampus sparing whole brain radiation therapy (HS-WBRT) has been shown to reduce the incidence of memory loss. In this study, we found that multi-field intensity modulated radiation therapy (IMRT), with strict constraints to the brain parenchyma and to the hippocampus, reduces follicular scalp dose and prevents alopecia. METHODS: Suitable patients befitting the inclusion criteria of the RTOG 0933 trial received Hippocampus sparing whole brain radiation. On follow up, they were noticed to have full scalp hair preservation. 5 mm thickness of follicle bearing scalp in the radiation field was outlined in the planning CT scans. Conventional opposed lateral WBRT radiation fields were applied to these patient-specific image sets and planned with the same nominal dose of 30 Gy in 10 fractions. The mean and maximum dose to follicle bearing skin and Dose Volume Histogram (DVH) data were analyzed for conventional and HS-WBRT. Paired t-test was used to compare the means. RESULTS: All six patients had fully preserved scalp hair and remained clinically cognitively intact 1-3 months after HS-WBRT. Compared to conventional WBRT, in addition to the intended sparing of the Hippocampus, HS-WBRT delivered significantly lower mean dose (22.42 cGy vs. 16.33 cGy, p < 0.0001), V24 (9 cc vs. 44 cc, p < 0.0000) and V30 (9 cc vs. 0.096 cc, p = 0.0106) to follicle hair bearing scalp and prevented alopecia. There were no recurrences in the Hippocampus area. CONCLUSIONS: HS-WBRT, with an 11-field set up as described, while attempting to conserve hippocampus radiation and maintain radiation dose to brain inadvertently spares follicle-bearing scalp and prevents alopecia.Item Unknown Event memory: A theory of memory for laboratory, autobiographical, and fictional events.(Psychol Rev, 2015-01) Rubin, David C; Umanath, ShardaAn event memory is a mental construction of a scene recalled as a single occurrence. It therefore requires the hippocampus and ventral visual stream needed for all scene construction. The construction need not come with a sense of reliving or be made by a participant in the event, and it can be a summary of occurrences from more than one encoding. The mental construction, or physical rendering, of any scene must be done from a specific location and time; this introduces a "self" located in space and time, which is a necessary, but need not be a sufficient, condition for a sense of reliving. We base our theory on scene construction rather than reliving because this allows the integration of many literatures and because there is more accumulated knowledge about scene construction's phenomenology, behavior, and neural basis. Event memory differs from episodic memory in that it does not conflate the independent dimensions of whether or not a memory is relived, is about the self, is recalled voluntarily, or is based on a single encoding with whether it is recalled as a single occurrence of a scene. Thus, we argue that event memory provides a clearer contrast to semantic memory, which also can be about the self, be recalled voluntarily, and be from a unique encoding; allows for a more comprehensive dimensional account of the structure of explicit memory; and better accounts for laboratory and real-world behavioral and neural results, including those from neuropsychology and neuroimaging, than does episodic memory.Item Open Access Forebrain Acetylcholine in Action: Dynamic Activities and Modulation on Target Areas(2009) Zhang, HaoForebrain cholinergic projection systems innervate the entire cortex and hippocampus. These cholinergic systems are involved in a wide range of cognitive and behavioral functions, including learning and memory, attention, and sleep-waking modulation. However, the in vivo physiological mechanisms of cholinergic functions, particularly their fast dynamics and the consequent modulation on the hippocampus and cortex, are not well understood. In this dissertation, I investigated these issues using a number of convergent approaches.
First, to study fast acetylcholine (ACh) dynamics and its interaction with field potential theta oscillations, I developed a novel technique to acquire second-by-second electrophysiological and neurochemical information simultaneously with amperometry. Using this technique on anesthetized rats, I discovered for the first time the tight in vivo coupling between phasic ACh release and theta oscillations on fine spatiotemporal scales. In addition, with electrophysiological recording, putative cholinergic neurons in medial setpal area (MS) were found with firing rate dynamics matching the phasic ACh release.
Second, to further elucidate the dynamic activities and physiological functions of cholinergic neurons, putative cholinergic MS neurons were identified in behaving rats. These neurons had much higher firing rates during rapid-eye-movement (REM) sleep, and brief responses to auditory stimuli. Interestingly, their firing promoted theta/gamma oscillations, or small-amplitude irregular activities (SIA) in a state-dependent manner. These results suggest that putative MS cholinergic neurons may be a generalized hippocampal activation/arousal network.
Third, I investigated the hypothesis that ACh enhances cortical and hippocampal immediate-early gene (IEG) expression induced by novel sensory experience. Cholinergic transmission was manipulated with pharmacology or lesion. The resultant cholinergic impairment suppressed the induction of arc, a representative IEG, suggesting that ACh promotes IEG induction.
In conclusion, my results have revealed that the firing of putative cholinergic neurons promotes hippocampal activation, and the consequent phasic ACh release is tightly coupled to theta oscillations. These fast cholinergic activities may provide exceptional opportunities to dynamically modulate neural activity and plasticity on much finer temporal scales than traditionally assumed. By the subsequent promotion of IEG induction, ACh may further substantiate its function in neural plasticity and memory consolidation.
Item Open Access Functional neuroimaging of autobiographical memory.(2010) St. Jacques, Peggy L.Autobiographical memory (AM) refers to memory for events from our own personal past. Functional neuroimaging studies of AM are important because they can investigate the neural correlates of processes that are difficult to study using laboratory stimuli, including: complex constructive processes, subjective qualities of memory retrieval, and remote memory. Three functional magnetic resonance imaging (fMRI) studies are presented to examine these important contributions of AM. The first study investigates the neural correlates of temporal-order memory for autobiographical events using a novel photo paradigm. Participants took photographs at many campus locations over a period of several hours, and the following day they were scanned while making temporal-order judgments to pairs of photographs from different locations. It was found that temporal-order decisions associated with recollection recruited left prefrontal (PFC) and left posterior parahippocampal cortex, whereas temporal-order decisions relying on familiarity recruited greater activity in the right PFC. The second study examines self-projection, the capacity to re-experience the personal past and to mentally infer another person’s perspective. A novel camera technology was used to examine self-projection by prospectively generating dynamic visuospatial images taken from a first-person perspective. Participants were literally asked to self-project into the personal past or into the life of another person. Self-projection of one’s own past self recruited greater ventral medial PFC (mPFC), and self-projection of another individual recruited dorsal mPFC. Activity in ventral vs. dorsal mPFC was also sensitive to the ability to relive or understand the perspective taken on each trial. Further, task-related functional connectivity analysis revealed that ventral mPFC contributed to the medial temporal lobe network linked to memory processes, whereas dorsal mPFC contributed to the frontoparietal network linked to controlled processes. The third study focuses on the neural correlates underlying age-related differences in the recall of episodically rich AMs. Age-related attenuation in the episodic richness of AM was linked to reductions in activity elicited during elaboration. Age effects on AM were more pronounced during elaboration than search, with older adults showing less sustained recruitment of the hippocampus and ventrolateral PFC for less episodically rich AMs. Further, there was an age-related reduction in the top-down modulation of the PFC on the hippocampus by episodic richness, possibly reflecting fewer controlled processes operating on the recovery of information in the hippocampus. Ultimately, the goal of all memory research is to understand how memory operates in the real-world; the present research highlights the important contribution of functional neuroimaging studies of AM in attaining this goal.Item Open Access Hippocampal Avoidance in Multi-Target Radiosurgery(2021) Gude, Zachary WilliamBrain metastases can occur in 20%-40% of cancer patients. Single isocenter multi-target (SIMT) radiosurgery planned with volumetric modulated arc therapy (VMAT) is a method of treating multiple brain metastases simultaneously. These treatments deliver high doses which emphasizes the need for accuracy and avoidance of critical neurological structures to maintaining a patient’s quality of life (QOL). QOL is highly correlated to patient memory, suggesting the hippocampus as a critical structure to avoid in treatment due to its significant role in episodic memory development. Radiosurgery treatments commonly use specialized MLC leaves (HD) that have a narrower width to improve dose conformity around metastases. This work serves to evaluate the feasibility of avoiding the hippocampus in SIMT treatments using VMAT based on MLC leaf width, as well as the effects of hippocampal avoidance on plan quality.40 patients, each previously treated with SIMT planned with VMAT for between 4-10 brain metastases using HD-MLCs, enrolled in an IRB approved protocol. The plans were evaluated for meeting RTOG 0933 recommended dose constraints to the hippocampus. If constraints were not met, then treatments were replanned with optimization objectives added to the hippocampus and/or arc orientation adjustments to meet constraints without compromising target coverage or other organ-at-risk (OAR) dose constraints. Afterwards, the treatments both with and without hippocampal objectives were replanned using standard width MLC leaves (SD-MLCs). All 4 plan types were then evaluated for plan quality using conformity index, V20%[cc], V50%[cc], V75%[cc] and D50%[cGy]. 8 total hippocampi across 7 patient plans exceeded constraints. 4 of these hippocampi could be spared through optimization objective adjustment, and 1 more with an arc orientation adjustment. Biological effective dose (BED) to the 8 hippocampi decreased by 29% ± 23% (p= 0.007) with no significant changes in dose to normal tissue when planned with the addition of hippocampal objectives. SD-MLCs showed similar results, sparing the same 5 of the 8 hippocampi exceeding constraints, but also increased dose to healthy tissue, most substantially in V20%[cc] which increased 59.56% ± 53% (p= 0.015) and 48.22% ± 32.17% (p= 0.0056) in plans with and without hippocampal objectives respectively. Also, in plans both with and without hippocampal optimization objectives, there was no significant change in conformity index when switching MLCs from HD to SD leaves. Meeting recommended hippocampal constraints was possible in 57% of patients that initially exceeded constraints. The ability to spare this structure was independent of MLC width, and correlated to the distance between the hippocampus and the nearest target. From this data set, the smallest distance avoidable was 0.45cm. All un-avoided hippocampi were at least touching a target, if not overlapped. The larger MLC leaves resulted in higher doses to larger volumes of normal tissue, however the planning technique of VMAT was able to meet target coverage without compromising treatment conformity when larger MLC leaves were used.
Item Open Access Hippocampus shape analysis and late-life depression.(PLoS One, 2008-03-19) Zhao, Zheen; Taylor, Warren D; Styner, Martin; Steffens, David C; Krishnan, K Ranga R; MacFall, James RMajor depression in the elderly is associated with brain structural changes and vascular lesions. Changes in the subcortical regions of the limbic system have also been noted. Studies examining hippocampus volumetric differences in depression have shown variable results, possibly due to any volume differences being secondary to local shape changes rather than differences in the overall volume. Shape analysis offers the potential to detect such changes. The present study applied spherical harmonic (SPHARM) shape analysis to the left and right hippocampi of 61 elderly subjects with major depression and 43 non-depressed elderly subjects. Statistical models controlling for age, sex, and total cerebral volume showed a significant reduction in depressed compared with control subjects in the left hippocampus (F(1,103) = 5.26; p = 0.0240) but not right hippocampus volume (F(1,103) = 0.41; p = 0.5213). Shape analysis showed significant differences in the mid-body of the left (but not the right) hippocampus between depressed and controls. When the depressed group was dichotomized into those whose depression was remitted at time of imaging and those who were unremitted, the shape comparison showed remitted subjects to be indistinguishable from controls (both sides) while the unremitted subjects differed in the midbody and the lateral side near the head. Hippocampal volume showed no difference between controls and remitted subjects but nonremitted subjects had significantly smaller left hippocampal volumes with no significant group differences in the right hippocampus. These findings may provide support to other reports of neurogenic effects of antidepressants and their relation to successful treatment for depressive symptoms.Item Open Access Imagery and retrieval of auditory and visual information: neural correlates of successful and unsuccessful performance.(Neuropsychologia, 2011-06) Huijbers, Willem; Pennartz, Cyriel MA; Rubin, David C; Daselaar, Sander MRemembering past events - or episodic retrieval - consists of several components. There is evidence that mental imagery plays an important role in retrieval and that the brain regions supporting imagery overlap with those supporting retrieval. An open issue is to what extent these regions support successful vs. unsuccessful imagery and retrieval processes. Previous studies that examined regional overlap between imagery and retrieval used uncontrolled memory conditions, such as autobiographical memory tasks, that cannot distinguish between successful and unsuccessful retrieval. A second issue is that fMRI studies that compared imagery and retrieval have used modality-aspecific cues that are likely to activate auditory and visual processing regions simultaneously. Thus, it is not clear to what extent identified brain regions support modality-specific or modality-independent imagery and retrieval processes. In the current fMRI study, we addressed this issue by comparing imagery to retrieval under controlled memory conditions in both auditory and visual modalities. We also obtained subjective measures of imagery quality allowing us to dissociate regions contributing to successful vs. unsuccessful imagery. Results indicated that auditory and visual regions contribute both to imagery and retrieval in a modality-specific fashion. In addition, we identified four sets of brain regions with distinct patterns of activity that contributed to imagery and retrieval in a modality-independent fashion. The first set of regions, including hippocampus, posterior cingulate cortex, medial prefrontal cortex and angular gyrus, showed a pattern common to imagery/retrieval and consistent with successful performance regardless of task. The second set of regions, including dorsal precuneus, anterior cingulate and dorsolateral prefrontal cortex, also showed a pattern common to imagery and retrieval, but consistent with unsuccessful performance during both tasks. Third, left ventrolateral prefrontal cortex showed an interaction between task and performance and was associated with successful imagery but unsuccessful retrieval. Finally, the fourth set of regions, including ventral precuneus, midcingulate cortex and supramarginal gyrus, showed the opposite interaction, supporting unsuccessful imagery, but successful retrieval performance. Results are discussed in relation to reconstructive, attentional, semantic memory, and working memory processes. This is the first study to separate the neural correlates of successful and unsuccessful performance for both imagery and retrieval and for both auditory and visual modalities.