Functional Role of Neurogenesis in Humans

Functional Role of Neurogenesis in Humans Self-renewing stem-like cells in the adult hippocampus have captured the imagination of neuroscientists and clinicians for decades. Unfortunately, there have been relatively few studies investigating the functional role of AHN in humans. Throughout this thesis, I have described a number of studies in which we undertook the challenge of identifying indirect correlates of AHN in humans as well as elucidating the functional role of adult-born granule cells in everyday memory. We accomplished this by assessing various lifestyle- and blood-based factors known to influence neurogenesis from the animal literature and comparing these factors to behavioural performance on tasks which tested the proposed roles for AHN in learning and memory. There has been much speculation regading the functional role of neurogenesis in humans. Computational modellers and theorists have proposed several distinct roles for AHN in cognition based on what is known of their location in the brain, functional connectivity with surrounding regions and physiological poperties. Some have proposed that the constant turnover of newborn cells in the hippocampus would allow memory storage for novel events, while avoiding interference with older memories, a computational process termed pattern separation (Becker et al., 2005; Chambers and Conroy, 2007; Appleby and Wiskott, 2009; Becker et al., 2009; Weisz and Argibay, 2009; Aimone and Gage, 2011). However, events occurring close together in time may be subject to enhanced interference because the same population of cells would be firing in response to each event encountered. This process of increasing interference between events occurring close together in time is referred to as pattern integration (A imone et al., 2006). Indeed, some studies have shown paradoxical improvements in working memory tasks following ablation of neurogenesis (Saxe et al., 2007). However, working memory circuits outside of the hippocampus may be responsible for such improvements. Across short timescales, the majority of behavioural evidence from rodents has actually demonstrated that the role for neurogenesis in cognition, although seemingly widespread, converges on one function in particular. The formation of context-shock associations is impaired in animals lacking neurogenesis (Saxe et al., 2006; Winocur et al., 2006; Imayoshi et al., 2008; Warner-Schmidt et al., 2008; Wojtowicz et al., 2008; Hernandez-Rabaza et al., 2009; Ko et al., 2009; Guo et al., 2011; Nakashiba et al., 2012; Pan et al., 2012b), especially when the shock is relatively weak or training paradigm relatively short (Drew et al., 2010; Pan et al., 2012a, 2013). Animals lacking neurogenesis are also impaired at discriminating between o verlapping odor pairs (Luu et al., 2012) or between nearby, but not far apart spatial locations (Clelland et al., 2009). In contrast, upregualting neurogenesis via aerobic exercise or genetic manipulation has been shown to increase AHN and leads to enhanced behavioural pattern separation or CFC performance (Creer et al., 2010; Sahay et al., 2011; Kohman et al., 2012). While it seems like a wide-variety of tasks require adult-born granule cells, many, if not all of these tasks require overcoming interference. All of these tasks require the animal to form separate representations of similar stimuli, regardless of whether the stimuli are different contexts, objects, spatial locations or odours. This is why I say that AHN is required for a wide-variety, yet specific set of memory tasks. The behavioural requirements of tasks shown to depend on neurogenesis have differed substantially, but the psychological construct shown to rely on AHN has been fairly consistent. Neurogenesis may further help separate similar events occurring over longer time periods (Becker, 2005; Aimone et al., 2006; Becker and Wojtowicz, 2007). A distinct pool of newborn neurons would help to add a degree of contextual novelty to similar events that are separated by a sufficient amount of time. Without new cells being added to the hippocampal network, the same populations of cells would end up reperesenting multiple different memories, leading to catastrophic interference (Wiskott et al., 2006). This account of the role for neurogenesis in learning and memory has generally been reffered to as the memory retention hypothesis throughout this thesis. In contrast, others have proposed that the addition of newborn cells to the hippocampus would result in existing connections being altered in such a way that information is lost (Feng et al., 2001; Deisseroth et al., 2004; Frankland et al., 2013). This account of the role for neurogenesis in learning and memory has generally been referred to as the memory clearance hypothesis throughout this thesis. Behavioural evidence from non-human animal studies has supported the memory retention hypothesis, especially for spatial or context-rich memories. For instance, rodents with ablated neurogenesis display marked deficits in remembering the platform locaton following MWM training across long, but not short timescales (Snyder et al., 2005; Deng et al., 2009; Jessberger et al., 2009; Kitamura et al., 2009; Inokuchi, 2011; Pan et al., 2012a, 2012b, 2013). In contrast, some studies have shown impaired long-term retention of fear memories in younger mice with relatively high rates of neurogenesis compared to their older counterparts (Akers et al., 2012). When older mice had wheel-running- or antidepressant drug-induced enhancement of neurogenesis, they were impaired on tests of remote memory compared to control mice (Akers et al., 2014). Therefore, it would seem that behavioural evidence from rodents has also supported the memory clearance hypothesis. The persistence or clearance of memories as a result of ongoing neural turnover in the DG may depend on the type of memory. There is evidence to suggest that spatial memories are always dependent on the hippocampus (Snyder et al., 2005; Deng et al., 2009; Jessberger et al., 2009). For these memories that are permanently hippocampal-dependent, AHN may help keep overlapping events disctinct from one another, thereby promoting long-term retention of the original memory. On the other hand, fear memories may be supported by regions outside of the hippocampus (Kitamura et al., 2009). Thus, for those memories that can be supported by extrahippocampal structures, AHN may accelerate the process of systems consolidation (Kitamura et al., 2009), shifting the dependence of the memory from the hippocampus to neocortical regions (McClelland et al., 1995; Squire and Alvarez, 1995; Maviel et al., 2004; Squire and Bayley, 2007). While animal studies have provided val uable clues as to the importance of AHN in learning and memory, it has nonetheless become apparent that studying the functional role of neurogenesis directly in humans is the critical next step that must be taken in order to alleviate some of the confusion generated in non-human animal studies. In the set of studies that comprise this thesis, we have demonstrated that change in aerobic capacity following chronic physical activity correlates with change in performance on a putatively neurogenesis-dependent visual pattern separation task. On the other hand, stress and depression scores had opposing effects on behavioural pattern separation performance. Importantly, neither exercise response nor depression scores predicted performance on other trial types within the BPS-O, repeated or novel items, nor the visuo-spatial CANTAB ® PAL task. We have also shown that lower stress and depression scores are associated with improved visual object recognition on repeated items following a two-week delay from the study phase. Further, on two-week delayed retention tests, participants scored near chance at identifying lures as â€Å"similar†, regardless of stress and depression levels. Interestingly, they more often misclassified these items as â€Å"new†, as opposed to â €Å"old†. Our results provide indirect evidence from human participants that AHN is important for pattern separation across shorter delays, while contributing to the persistence of memories for repeated items across extended time intervals. Future studies could explicitly test the memory clearance hypothesis in humans by measuring recognition memory across longer timescales with a pro-neurogenic intervention, such as long-term exercise, in between study and test. Pattern separation and memory retention (or clearance) may be coexisting phenomena. The addition of immature neurons to the hippocampus may at first bias the network towards pattern separation, as opposed to pattern completion, thereby reducing interference between events (Yassa and Reagh, 2013). In turn, the amount of pattern separation may decide what information will be subject to reconsolidation and what information will be cleared (Yassa and Reagh, 2013). Reconsolidation is the process whereby an existing memory becomes susceptible to change. If an event is considered similar, but not the same as, a previously stored event then the original memory may be modified to accommodate the discrepent information. Thus, the constant addition of adult-born neurons to the hippocampus may serve as a means of adding contextual information to existing memories. However, the original memory may be altered so drastically during reconsolidation that it is no longer accessible (essentially cleare d), depending on the amount of interference between the original memory and the novel event. Indeed, a number of computational models predict that the addition of newborn neurons to an existing circuit would hinder retrieval of previously stored memories (Deisseroth et al., 2004; Weisz and Argibay, 2009, 2012). On the other hand, if two events are considered one in the same, then information may be strengthened, although more generalized in nature. As these adult-born neurons that once contributed to pattern integration or pattern separation continue to mature and establish new synaptic connections with the pre-existing circuitry, they may destabilize previously established memories in the hippocampus, leading to the loss of previously stored information (Josselyn and Frankland, 2012; Frankland et al., 2013; Yassa and Reagh, 2013). In turn, the clearance of older memories would make room for new ones and the newborn neurons would become part of the physical storage site for new memo ries (Josselyn and Frankland, 2012). Thus, both processes may be beneficial in their own way. Whether or not memory clearance is a benefit or detriment to memory performance really depends on the relative importance of information is being cleared. Correlates of Neurogenesis in Humans and Animals Neurogenesis is down-regulated in a variety of neuropsychiatric disorders, so being able to characterize AHN in vivo is critical for better disease prevention and/or treatment. Unfortunately, there is no way to non-invasively quantify newborn cells in the living human hippocampus. Therefore, it has been difficult to improve our understanding of how neurogenesis influences the onset or recovery from certain disorders associated with downregulated neurogenesis, such as depression. In addition, we cannot assess the specific contribution of newborn neurons to learning and memory.

A Game of Thrones Chapter Thirty-five

Eddard He found Littlefinger in the brothel's common room, chatting amiably with a tall, elegant woman who wore a feathered gown over skin as black as ink. By the hearth, Heward and a buxom wench were playing at forfeits. From the look of it, he'd lost his belt, his cloak, his mail shirt, and his right boot so far, while the girl had been forced to unbutton her shift to the waist. Jory Cassel stood beside a rain-streaked window with a wry smile on his face, watching Heward turn over tiles and enjoying the view. Ned paused at the foot of the stair and pulled on his gloves. â€Å"It's time we took our leave. My business here is done.† Heward lurched to his feet, hurriedly gathering up his things. â€Å"As you will, my lord,† Jory said. â€Å"I'll help Wyl bring round the horses.† He strode to the door. Littlefinger took his time saying his farewells. He kissed the black woman's hand, whispered some joke that made her laugh aloud, and sauntered over to Ned. â€Å"Your business,† he said lightly, â€Å"or Robert's? They say the Hand dreams the king's dreams, speaks with the king's voice, and rules with the king's sword. Does that also mean you fuck with the king's—† â€Å"Lord Baelish,† Ned interrupted, â€Å"you presume too much. I am not ungrateful for your help. It might have taken us years to find this brothel without you. That does not mean I intend to endure your mockery. And I am no longer the King's Hand.† â€Å"The direwolf must be a prickly beast,† said Littlefinger with a sharp twist of his mouth. A warm rain was pelting down from a starless black sky as they walked to the stables. Ned drew up the hood of his cloak. Jory brought out his horse. Young Wyl came right behind him, leading Littlefinger's mare with one hand while the other fumbled with his belt and the lacings of his trousers. A barefoot whore leaned out of the stable door, giggling at him. â€Å"Will we be going back to the castle now, my lord?† Jory asked. Ned nodded and swung into the saddle. Littlefinger mounted up beside him. Jory and the others followed. â€Å"Chataya runs a choice establishment,† Littlefinger said as they rode. â€Å"I've half a mind to buy it. Brothels are a much sounder investment than ships, I've found. Whores seldom sink, and when they are boarded by pirates, why, the pirates pay good coin like everyone else.† Lord Petyr chuckled at his own wit. Ned let him prattle on. After a time, he quieted and they rode in silence. The streets of King's Landing were dark and deserted. The rain had driven everyone under their roofs. It beat down on Ned's head, warm as blood and relentless as old guilts. Fat drops of water ran down his face. â€Å"Robert will never keep to one bed,† Lyanna had told him at Winterfell, on the night long ago when their father had promised her hand to the young Lord of Storm's End. â€Å"I hear he has gotten a child on some girl in the Vale.† Ned had held the babe in his arms; he could scarcely deny her, nor would he lie to his sister, but he had assured her that what Robert did before their betrothal was of no matter, that he was a good man and true who would love her with all his heart. Lyanna had only smiled. â€Å"Love is sweet, dearest Ned, but it cannot change a man's nature.† The girl had been so young Ned had not dared to ask her age. No doubt she'd been a virgin; the better brothels could always find a virgin, if the purse was fat enough. She had light red hair and a powdering of freckles across the bridge of her nose, and when she slipped free a breast to give her nipple to the babe, he saw that her bosom was freckled as well. â€Å"I named her Barra,† she said as the child nursed. â€Å"She looks so like him, does she not, milord? She has his nose, and his hair . . . â€Å" â€Å"She does.† Eddard Stark had touched the baby's fine, dark hair. It flowed through his fingers like black silk. Robert's firstborn had had the same fine hair, he seemed to recall. â€Å"Tell him that when you see him, milord, as it . . . as it please you. Tell him how beautiful she is.† â€Å"I will,† Ned had promised her. That was his curse. Robert would swear undying love and forget them before evenfall, but Ned Stark kept his vows. He thought of the promises he'd made Lyanna as she lay dying, and the price he'd paid to keep them. â€Å"And tell him I've not been with no one else. I swear it, milord, by the old gods and new. Chataya said I could have half a year, for the baby, and for hoping he'd come back. So you'll tell him I'm waiting, won't you? I don't want no jewels or nothing, just him. He was always good to me, truly.† Good to you, Ned thought hollowly. â€Å"I will tell him, child, and I promise you, Barra shall not go wanting.† She had smiled then, a smile so tremulous and sweet that it cut the heart out of him. Riding through the rainy night, Ned saw Jon Snow's face in front of him, so like a younger version of his own. If the gods frowned so on bastards, he thought dully, why did they fill men with such lusts? â€Å"Lord Baelish, what do you know of Robert's bastards?† â€Å"Well, he has more than you, for a start.† â€Å"How many?† Littlefinger shrugged. Rivulets of moisture twisted down the back of his cloak. â€Å"Does it matter? If you bed enough women, some will give you presents, and His Grace has never been shy on that count. I know he's acknowledged that boy at Storm's End, the one he fathered the night Lord Stannis wed. He could hardly do otherwise. The mother was a Florent, niece to the Lady Selyse, one of her bedmaids. Renly says that Robert carried the girl upstairs during the feast, and broke in the wedding bed while Stannis and his bride were still dancing. Lord Stannis seemed to think that was a blot on the honor of his wife's House, so when the boy was born, he shipped him off to Renly.† He gave Ned a sideways glance. â€Å"I've also heard whispers that Robert got a pair of twins on a serving wench at Casterly Rock, three years ago when he went west for Lord Tywin's tourney. Cersei had the babes killed, and sold the mother to a passing slaver. Too much an affront to Lannister pride, that close to home.† Ned Stark grimaced. Ugly tales like that were told of every great lord in the realm. He could believe it of Cersei Lannister readily enough . . . but would the king stand by and let it happen? The Robert he had known would not have, but the Robert he had known had never been so practiced at shutting his eyes to things he did not wish to see. â€Å"Why would Jon Arryn take a sudden interest in the king's baseborn children?† The short man gave a sodden shrug. â€Å"He was the King's Hand. Doubtless Robert asked him to see that they were provided for.† Ned was soaked through to the bone, and his soul had grown cold. â€Å"It had to be more than that, or why kill him?† Littlefinger shook the rain from his hair and laughed. â€Å"Now I see. Lord Arryn learned that His Grace had filled the bellies of some whores and fishwives, and for that he had to be silenced. Small wonder. Allow a man like that to live, and next he's like to blurt out that the sun rises in the east.† There was no answer Ned Stark could give to that but a frown. For the first time in years, he found himself remembering Rhaegar Targaryen. He wondered if Rhaegar had frequented brothels; somehow he thought not. The rain was falling harder now, stinging the eyes and drumming against the ground. Rivers of black water were running down the hill when Jory called out, â€Å"My lord,† his voice hoarse with alarm. And in an instant, the street was full of soldiers. Ned glimpsed ringmail over leather, gauntlets and greaves, steel helms with golden lions on the crests. Their cloaks clung to their backs, sodden with rain. He had no time to count, but there were ten at least, a line of them, on foot, blocking the street, with longswords and iron-tipped spears. â€Å"Behind!† he heard Wyl cry, and when he turned his horse, there were more in back of them, cutting off their retreat. Jory's sword came singing from its scabbard. â€Å"Make way or die!† â€Å"The wolves are howling,† their leader said. Ned could see rain running down his face. â€Å"Such a small pack, though.† Littlefinger walked his horse forward, step by careful step. â€Å"What is the meaning of this? This is the Hand of the King.† â€Å"He was the Hand of the King.† The mud muffled the hooves of the blood bay stallion. The line parted before him. On a golden breastplate, the lion of Lannister roared its defiance. â€Å"Now, if truth be told, I'm not sure what he is.† â€Å"Lannister, this is madness,† Littlefinger said. â€Å"Let us pass. We are expected back at the castle. What do you think you're doing?† â€Å"He knows what he's doing,† Ned said calmly. Jaime Lannister smiled. â€Å"Quite true. I'm looking for my brother. You remember my brother, don't you, Lord Stark? He was with us at Winterfell. Fair-haired, mismatched eyes, sharp of tongue. A short man.† â€Å"I remember him well,† Ned replied. â€Å"It would seem he has met some trouble on the road. My lord father is quite vexed. You would not perchance have any notion of who might have wished my brother ill, would you?† â€Å"Your brother has been taken at my command, to answer for his crimes,† Ned Stark said. Littlefinger groaned in dismay. â€Å"My lords—† Ser Jaime ripped his longsword from its sheath and urged his stallion forward. â€Å"Show me your steel, Lord Eddard. I'll butcher you like Aerys if I must, but I'd sooner you died with a blade in your hand.† He gave Littlefinger a cool, contemptuous glance. â€Å"Lord Baelish, I'd leave here in some haste if I did not care to get bloodstains on my costly clothing.† Littlefinger did not need to be urged. â€Å"I will bring the City Watch,† he promised Ned. The Lannister line parted to let him through, and closed behind him. Littlefinger put his heels to his mare and vanished around a corner. Ned's men had drawn their swords, but they were three against twenty. Eyes watched from nearby windows and doors, but no one was about to intervene. His party was mounted, the Lannisters on foot save for Jaime himself. A charge might win them free, but it seemed to Eddard Stark that they had a surer, safer tactic. â€Å"Kill me,† he warned the Kingslayer, â€Å"and Catelyn will most certainly slay Tyrion.† Jaime Lannister poked at Ned's chest with the gilded sword that had sipped the blood of the last of the Dragonkings. â€Å"Would she? The noble Catelyn Tully of Riverrun murder a hostage? I think . . . not.† He sighed. â€Å"But I am not willing to chance my brother's life on a woman's honor.† Jaime slid the golden sword into its sheath. â€Å"So I suppose I'll let you run back to Robert to tell him how I frightened you. I wonder if he'll care.† Jaime pushed his wet hair back with his fingers and wheeled his horse around. When he was beyond the line of swordsmen, he glanced back at his captain. â€Å"Tregar, see that no harm comes to Lord Stark.† â€Å"As you say, m'lord.† â€Å"Still . . . we wouldn't want him to leave here entirely unchastened, so†Ã¢â‚¬â€through the night and the rain, he glimpsed the white of Jaime's smile—†kill his men.† â€Å"No!† Ned Stark screamed, clawing for his sword. Jaime was already cantering off down the street as he heard Wyl shout. Men closed from both sides. Ned rode one down, cutting at phantoms in red cloaks who gave way before him. Jory Cassel put his heels into his mount and charged. A steel-shod hoof caught a Lannister guardsman in the face with a sickening crunch. A second man reeled away and for an instant Jory was free. Wyl cursed as they pulled him off his dying horse, swords slashing in the rain. Ned galloped to him, bringing his longsword down on Tregar's helm. The jolt of impact made him grit his teeth. Tregar stumbled to his knees, his lion crest sheared in half, blood running down his face. Heward was hacking at the hands that had seized his bridle when a spear caught him in the belly. Suddenly Jory was back among them, a red rain flying from his sword. â€Å"No!† Ned shouted. â€Å"Jory, away!† Ned's horse slipped under him and came crashing down in th e mud. There was a moment of blinding pain and the taste of blood in his mouth. He saw them cut the legs from Jory's mount and drag him to the earth, swords rising and failing as they closed in around him. When Ned's horse lurched back to its feet, he tried to rise, only to fall again, choking on his scream. He could see the splintered bone poking through his calf. It was the last thing he saw for a time. The rain came down and down and down. When he opened his eyes again, Lord Eddard Stark was alone with his dead. His horse moved closer, caught the rank scent of blood, and galloped away. Ned began to drag himself through the mud, gritting his teeth at the agony in his leg. It seemed to take years. Faces watched from candlelit windows, and people began to emerge from alleys and doors, but no one moved to help. Littlefinger and the City Watch found him there in the street, cradling Jory Cassel's body in his arms. Somewhere the gold cloaks found a litter, but the trip back to the castle was a blur of agony, and Ned lost consciousness more than once. He remembered seeing the Red Keep looming ahead of him in the first grey light of dawn. The rain had darkened the pale pink stone of the massive walls to the color of blood. Then Grand Maester Pycelle was looming over him, holding a cup, whispering, â€Å"Drink, my lord. Here. The milk of the poppy, for your pain.† He remembered swallowing, and Pycelle was telling someone to heat the wine to boiling and fetch him clean silk, and that was the last he knew.

Photochemical Synthesis of Benzopinacol and Its...

Photochemical Synthesis of Benzopinacol and its Acid-Catalyzed Rerrangement Product Benzopinacolone M.E.G. Balita Institute of Chemistry, University of Philippines, Diliman, Quezon City Date Performed: February 18, 2011 Date Submitted: March 4, 2011 Abstract In this experiment it is aimed to synthesize benzopinacol through photochemical reaction of benzophenone and, benzopinacolone via acid-catalyzed rearrangement of benzopinacol. In this experiment, mixture of benzophenone, isopropyl alcohol and a drop of glacial acetic acid was exposed to sunlight which in turn, undergone photochemical reaction. In this reaction, molecules of benzophenone was brought to n((* triplet state where it possibly abstracted hydrogen from isopropyl†¦show more content†¦Then, a shift is observed by one of the atoms to the carbocation. And finally, to stabilize the molecule, catalyst is then regenerated to yield the final product. In this experiment, benzopinacol is to be synthesized through photochemical reaction from benzophenone and benzopinacolone via acid-catalyzed rearrangement of benzopinacol. II. Methodology In this experiment, benzopinacol was to be synthesized through photochemical reaction and its acid-catalyzed rearrangement product benzopinacolone. Synthesis of Benzopinacol In this synthesis, 2.0g of benzophenone was dissolved in 50ml isopropyl alcohol in 50ml Erlenmeyer flask. In this solution, one drop of glacial acetic acid was added. It was then filled with isopropyl alcohol up to the brim. After, the flask was stoppered using a well-rolled cork. It was ensured that very little air as possible was trapped inside the flask. It was tightly bind using a parafilm. The flask was inverted and exposed to sunlight outside the laboratory. After all additional product ceased to form, the reaction mixture was cooled in an ice bath to allow precipitation of benzopinacol. The final product was then filtered off from the solution using a Buchener funnel. Its melting point, yield and infrared spetrum was then obtained. The Acid-Catalyzed Rearrangement of Benzopinacol In this synthesis, in a test tube, 2.5ml of glacial acetic acid

`` The Yellow Wallpaper `` By Charlotte Perkins Gilm...

Charlotte Perkins Gilman’s deconstruction of gender roles in The Yellow Wallpaper. AP English 12 Mr. AuCoin Shane Caswell October 1, 2015 Shane Caswell 1 Charlotte Perkins Gilman’s The Yellow Wallpaper is an interesting story told from the journals of a woman who progressively loses her mind being locked in her bedroom, but underneath the surface this short story shows us a woman who is at first confined by, but progressively freed from the gender roles and expectations put upon her by society and her spouse. This story is written in an epistolary format. This first-person narrative gives the reader an intimate portrayal of the social attitudes that were common in Victorian era England. From this perspective the story attacks the oppressed role forced onto women in Victorian society. The nameless narrator of the story is symbolic for all women in the late 1800s, a prisoner of a confining, patriarchal society. Women are expected to bear children, keep house and do only as they are told; in the narrator’s insanity, she defies these roles in possibly the most exaggerated sense. The husband of our narrator, John, represents society as a whole, and much like society he is controlling and he determines what the narrator (women) should and should not be doing, leaving her incapable of making decisions for herself. John is a man and a physician, so his â€Å"I know best† attitude can be attributed to his social status. He is very factual, scientific and likes to focus