I'm taking a class on psycholinguistics right now, and the aspect of localization is absolutely fascinating. In the class we keep a weekly journal, so this is the stuff I've been thinking about in relation the brain and language.
It is extraordinary that there are areas of the brain known as language areas, and even more extraordinary there there are those who seek to map those connections at an even deeper and more micro level. The idea of mapping the cellular connections associated with something as seemingly abstract as language seems so daunting, and yet the technology that exists today, especially TMS, introduces the possibility of such a thing.
What makes language so difficult to study is that it is so much more than words; it is the meaning of those words, the application of that meaning, the physical nature of producing them ouside of the brain, and, most cryptic, producing them in the brain as well, as thoughts. The fact that Wernicke's area is at a crossroads of three of the lobes implies that this region is, above all else, a junction of the regions of the brain involved in a variety of types of sensations, perceptions and motor function. Language, as it is represented in its physical localization, can be seen as an expression of so many other processes taking place. To map such connections on a cellular or molecular level would be to scientifically understand one of the higher processes that makes us "human".
The relationship between lesions or disorders of particular brain areas and the functional deficits with which they are associated is quite interesting. They are both the behavioural nature of the deficit itself, while at the same time being an important aspect of neuroanatomical research and functional localization. Aphasia is often brought up in neuroscience textbooks and the literature in the context of localization, and how it is important to our understanding of the various aspects of language and how they are represented physically in the brain. In neuropsychology and psychology, it is both that and also a loss of language capability. There are cases such as K.H., the architect who, after undergoing surgery to remove a tumor from Broca's area, initially lost his ability to speak and comprehend both the oral and written word (though he later regained some of what had been lost).
One wonders how anyone could function with such an extreme language deficit. Aphasia must feel incredibly disorienting; to have had full use of the faculties of language and then to lose them must be a very frustrating experience. As language is so essential in the experience of human life, it must make the aphasic person feel disconnected and confused. I am not suggesting that one dwell upon the horrors of aphasia when studying it, but rather that the behavioural effects emphasize not only the localization of language function in the brain, as well as the importance of language in the human world. Aphasia is one of many examples which show that to study language is so interesting because it is to study mind, brain and behaviour, and often all at once.
Sunday, January 23, 2011
Saturday, January 15, 2011
The crazy present/future cellular mapping
I am fascinated by brain imaging and electrophysiological stimulation, mainly because of the way in which it allows us to have a more minute understanding of the processes involved in functioning. The more micro we can get with these sorts of tests, the more we can actually understand the cellular and molecular mechanisms governing mental processes and behaviours. I read an article recently in Nature ("Neuroscience: Illuminating the brain", Buchen, 2010) about optogenetic manipulation, which is the opening of ion channels through opsin proteins injected via a virus; light stimulation triggers these opsin proteins at the cell membrane to open ion channels. This is a really neat new way of determining, with a great deal of specificity, the cellular networks involved in certain processes, and even crazier than that, the individual activity of cells within those networks. At this time, the light source is implanted through an "optrode" (an optic fibre and an electrode) into the skull of the animal when done in vivo, so there is no application for this on humans. As such, the more tantalizing higher functions we so desperately desire to map are still out of reach; but the neural networks involved in processes such as spatial learning can be measured in mice and rats. Optogenetic manipulation is also used quite successfully in vitro, which is actually how it was discovered. In 2005, Karl Diesseroth and Ed Boyden at Stanford University inserted a light sensitive channel (channelrhodopsin2) from green algae into neurons in a growing dish. They exposed these neurons to a pulse of blue light, and the channels opened, flooding positive ions into the neurons and causing them to fire. Optogenetic manipulation is going to change the mapping of cellular networks in a huge way.
Another thing that's going to change neurological mapping is that crazy connectome! If you haven't seen the TED talk on it (Sebastian Seung: "I am my connectome"):
My problem with this, other than the fact that the talk itself comes off as being a motivational speech, is that it doesn't seem to take synaptic plasticity into account. In fact, what it really doesn't take into account are the individual differences that arise from synaptic plasticity; but most importantly, that we, living our lives, are constantly altering the strength and weakness of connections in our brain. These neural connections are ever-changing and plastic. With every trafficked AMPA, with every hippocampal place cell reorganized, our synaptic circuitry is changing. Yes, it is ever-so-slight, but when what you are measuring is cells, ever-so-slight is pretty huge.
On the other hand, the idea of it being used to visualize mental illness by identifying miswiring of individual connections is pretty wild.
References
Buchen, L. (2010). Neuroscience: Illuminating the brain. Nature 465, 26-28.
Another thing that's going to change neurological mapping is that crazy connectome! If you haven't seen the TED talk on it (Sebastian Seung: "I am my connectome"):
My problem with this, other than the fact that the talk itself comes off as being a motivational speech, is that it doesn't seem to take synaptic plasticity into account. In fact, what it really doesn't take into account are the individual differences that arise from synaptic plasticity; but most importantly, that we, living our lives, are constantly altering the strength and weakness of connections in our brain. These neural connections are ever-changing and plastic. With every trafficked AMPA, with every hippocampal place cell reorganized, our synaptic circuitry is changing. Yes, it is ever-so-slight, but when what you are measuring is cells, ever-so-slight is pretty huge.
On the other hand, the idea of it being used to visualize mental illness by identifying miswiring of individual connections is pretty wild.
References
Buchen, L. (2010). Neuroscience: Illuminating the brain. Nature 465, 26-28.
Tuesday, April 13, 2010
Pinky and The Brain Teaches Basic Neuroanatomy
As someone partial to both the brain and The Brain, I think this is pretty fantastic:
Monday, April 5, 2010
So it turns out nicotine isn't all bad...
I’m taking this great class on drugs right now (well, this is the last week of classes, so not for much longer), and I was reading some articles on nicotine as a treatment for Parkinson's (!?!?!), and I learned something really neat. Apparently, nicotine can be used to reduce dyskinesias associated with the drug Levodopa (L-dopa), which is basically the gold standard in Parkinson’s treatment. Dyskinesias are abnormal involuntary movements (Quik et al., 2007), and are an uncomfortable side effect of the treatment. Since pretty much everyone with Parkinson’s takes L-dopa (and these side effects are fairly common), this is incredible news.
Quik, O’Leary & Tanner (2008) do a great job of outlining the nicotinic and dopaminergic interactions in the nigrostriatal region (see below for references to the articles). Their study explains that presynaptic nicotinic receptors regulate dopamine release, and dopamine receptor antagonists can block nicotine-evoked changes in locomotor activity (Quik et al., 2008), two key aspects in understanding the basis behind treating the side effects of L-dopa with nicotine.
Quik, Cox, Parameswaran, O’Leary, Langston & DiMonte (2007) hypothesize that the cholinergic system may play a role in modulating L-dopa-induced dyskinesias. Their study, using non-human primates, gives results that support this idea, too... they also postulate in their discussion that nicotine may even directly influence postsynaptic nicotine receptors, which in turn modulate other neurotransmitter systems which are implicated in dyskinesias (2007). This theory on postsynaptic involvement is supported by the preservation of nigrostriatal function associated with chronic nicotine administration (Quik et al., 2007).
Now, to be clear, nicotine does not regenerate areas of the nigrostriatal region that are damaged in Parkinson’s (Huang et al., 2009). Studies do show, however, that it is quite effective as a both a neuroprotective agent when given prior to nigrostriatal damage, as well as being useful in non-human primates and rats in attenuating the side effects of L-dopa. Pretty amazing stuff.
References
Huan L. Z., Parameswaran, N., Bordia, T., McIntosh, J. M., Quik, M. (2009). Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys. Journal of Neurochemistry, 109: 826-837.
Quik, M., Cox, H., Parameswaran, N., O’Leary, K., Langston, J. W., DiMonte, D., (2007). Nicotine Reduces Levodopa-Induced Dyskinesias in Lesioned Monkeys. Annals of Neurology, Vol. 62, 3: 1-9.
Quik, M., O’Leary, K. Tanner, C. M. (2008). Nicotine and Parkinson’s Disease: Implications for Therapy. Movement Disorders, Vol. 23, 12: 1641–1652.
Not referenced, but also really interesting on the same topic:
Bordias, T., Campos, C., Huang, L., Quik, M. (2008). Continuous and Intermittent Nicotine Treatment Reduces l-3,4-Dihydroxyphenylalanine (l-DOPA)-Induced Dyskinesias in a Rat Model of Parkinson's Disease. The Journal of Pharmacology and Experimental Therapeutics, 327: 239-247.
Quik, O’Leary & Tanner (2008) do a great job of outlining the nicotinic and dopaminergic interactions in the nigrostriatal region (see below for references to the articles). Their study explains that presynaptic nicotinic receptors regulate dopamine release, and dopamine receptor antagonists can block nicotine-evoked changes in locomotor activity (Quik et al., 2008), two key aspects in understanding the basis behind treating the side effects of L-dopa with nicotine.
Quik, Cox, Parameswaran, O’Leary, Langston & DiMonte (2007) hypothesize that the cholinergic system may play a role in modulating L-dopa-induced dyskinesias. Their study, using non-human primates, gives results that support this idea, too... they also postulate in their discussion that nicotine may even directly influence postsynaptic nicotine receptors, which in turn modulate other neurotransmitter systems which are implicated in dyskinesias (2007). This theory on postsynaptic involvement is supported by the preservation of nigrostriatal function associated with chronic nicotine administration (Quik et al., 2007).
Now, to be clear, nicotine does not regenerate areas of the nigrostriatal region that are damaged in Parkinson’s (Huang et al., 2009). Studies do show, however, that it is quite effective as a both a neuroprotective agent when given prior to nigrostriatal damage, as well as being useful in non-human primates and rats in attenuating the side effects of L-dopa. Pretty amazing stuff.
References
Huan L. Z., Parameswaran, N., Bordia, T., McIntosh, J. M., Quik, M. (2009). Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys. Journal of Neurochemistry, 109: 826-837.
Quik, M., Cox, H., Parameswaran, N., O’Leary, K., Langston, J. W., DiMonte, D., (2007). Nicotine Reduces Levodopa-Induced Dyskinesias in Lesioned Monkeys. Annals of Neurology, Vol. 62, 3: 1-9.
Quik, M., O’Leary, K. Tanner, C. M. (2008). Nicotine and Parkinson’s Disease: Implications for Therapy. Movement Disorders, Vol. 23, 12: 1641–1652.
Not referenced, but also really interesting on the same topic:
Bordias, T., Campos, C., Huang, L., Quik, M. (2008). Continuous and Intermittent Nicotine Treatment Reduces l-3,4-Dihydroxyphenylalanine (l-DOPA)-Induced Dyskinesias in a Rat Model of Parkinson's Disease. The Journal of Pharmacology and Experimental Therapeutics, 327: 239-247.
Sunday, March 21, 2010
In Defense of Vaccination
Due to the recent swine flu scare, the general question of whether or not to vaccinate has become a "hot topic" of sorts. I believe that this being a subject of debate arises from ignorance and a lack of understanding regarding how vaccination works and what it consists of, rearing its ugly head in the form of widespread propaganda. I recently read an excellent book which clears up a fair bit of misconception on the subject, and I highly recommend that everyone check it out. It's called Viruses, Plagues and History, by Michael B. A. Oldstone, published 2010. It is a fascinating read that is both infomative and entertaining.
Contrary to popular belief, immunity is not an absence of disease. It instead is referring to a "bodily system (immune response) that, instead of precluding infection, enables the infected host to respond to infection by resisting disease" (Oldstone, 2010). Here is how it works: antigens (the proteins in viruses and bacteria) trigger an immune response. If that immune response is successful, the body gains a long-term protection from the offending virus or bacteria (Oldstone, 2010). Much of the propaganda warning against vaccination presents the misinformed notion that an injection of the disease is dangerous in and of itself, which is untrue.
What a vaccine does is stimulate the immune system, preparing it with a blueprint of the virus or bacteria (Oldstone, 2010). There are 3 main types of techniques to create vaccinations that have proven successful:
1. attenuation, in which a live virus is passed through the tissue culture of an animal, decreasing the disease-causing ability of the virus (Oldstone, 2010). This produces a weakened form of the virus which causes an immune response but does not cause the disease itself. Vaccines using this technique include those for smallpox, measles and yellow fever.
2. the virus is killed using formalin and then tested for its ability to produce immune response. The Salk poliomyelitis vaccine uses this technique (Oldstone, 2010).
3. peparation of the viral subunit, recombinant or DNA vaccine (Oldstone, 2010). Hepatitis B vaccine is a recombinant vaccine.
As is evident in the above descriptions, none of these vaccines is a simple injection of the virus itself. Vaccines are not dangerous in essence (though this is not to say that there is no margin of error - which there is - but it is quite minute); as decribed in Oldstone's history of viruses and plagues (2010), they have proven to be safe and incredibly useful in the relative eradication of widespread contagions.
An interesting article on this subjects and its grander implications is here.
Contrary to popular belief, immunity is not an absence of disease. It instead is referring to a "bodily system (immune response) that, instead of precluding infection, enables the infected host to respond to infection by resisting disease" (Oldstone, 2010). Here is how it works: antigens (the proteins in viruses and bacteria) trigger an immune response. If that immune response is successful, the body gains a long-term protection from the offending virus or bacteria (Oldstone, 2010). Much of the propaganda warning against vaccination presents the misinformed notion that an injection of the disease is dangerous in and of itself, which is untrue.
What a vaccine does is stimulate the immune system, preparing it with a blueprint of the virus or bacteria (Oldstone, 2010). There are 3 main types of techniques to create vaccinations that have proven successful:
1. attenuation, in which a live virus is passed through the tissue culture of an animal, decreasing the disease-causing ability of the virus (Oldstone, 2010). This produces a weakened form of the virus which causes an immune response but does not cause the disease itself. Vaccines using this technique include those for smallpox, measles and yellow fever.
2. the virus is killed using formalin and then tested for its ability to produce immune response. The Salk poliomyelitis vaccine uses this technique (Oldstone, 2010).
3. peparation of the viral subunit, recombinant or DNA vaccine (Oldstone, 2010). Hepatitis B vaccine is a recombinant vaccine.
As is evident in the above descriptions, none of these vaccines is a simple injection of the virus itself. Vaccines are not dangerous in essence (though this is not to say that there is no margin of error - which there is - but it is quite minute); as decribed in Oldstone's history of viruses and plagues (2010), they have proven to be safe and incredibly useful in the relative eradication of widespread contagions.
An interesting article on this subjects and its grander implications is here.
Review of Studies on the Effects of Steroid Hormones on Learning and Memory
Steroid hormones influence a variety of physiological behaviours, including sexual behaviour, anxiety, learning and memory (Bidmon, 2003). As a result, many studies strive to correlate aspects of those behaviours; they are attempting to determine whether or not the hormones are causing the behaviours to influence each other. Based on the literature, steroid hormones such as cortisol are believed to enhance learning and memory, and this relationship is thought to be time-dependent. When the activity of these hormones occurs close in time to a particular behaviour or situation, they enhance learning and memory surrounding the event. This may be due to hormonal modulation of the AMPA and NMDA receptors; AMPA and NMDA receptors are involved in synaptic plasticity.
It also may be attributed to hormone receptors in circuits and areas of the brain that are specifically associated with learning and memory. The particular amount of the hormone is crucial: high levels of stress can be condusive to learning, but low levels of stress has shown to be detrimental. Further proving this relationship, the lesioning of areas associated with learning in ablation studies of mice blocks the stress-induced inversion of serial memory retrieval.
The steroid hormones of the adrenal cortex (the glucocorticoids and the mineralocorticoids) have been implicated in learning and memory. The glucocorticoids include cortisol and corticosterone, among others; what the glucocorticoids do is modulate carbohydrate metabolism by converting stored proteins into carbohydrates (Brown, 1994). Glucocorticoids (corticosteroids in rats) are released in response to stressful stimuli, and this response has been shown to have an effect on learning and memory. The hypothalamus produces corticotropin releasing hormone (CRH), which in turn stimulates adrenocorticotropic hormone (ACTH) release. ACTH is a pituitary hormone of the pars distalis, which then stimulates glucocorticoid release from the adrenal cortex. It is produced in the corticotroph cells of the adenohypophysis. Because of the three structures involved, these hormones are said to operate in a third-order feedback loop known as the hypothalamic-pituitary-adrenal (H-P-A) axis (Brown, 1994).
As shown by Akirav et al. (2004), the activation of this system causes emotionally charged experiences to alter memory storage. Glucocorticoids and mineralocorticoids bind to receptors in areas of the forebrain which play a role in emotional regulation, learning and memory processes (Berger, 2009). These receptors also “act as transcription factors and mediate complementary but also in part overlapping actions of corticosterone in endocrine and behavioural functions” (Berger, 2009). The effects of these the steroid hormones on LTP is presumed to be time-dependent; previous experiments in the hippocampal CA1 area describe the glucocorticoid corticosterone's facilitation of long-term potentiation in a rapid non-genomic fashion. This same hormone suppresses LTP that is induced several hours after the hormone's application (Krugers, 2007).
Bidmon et al. (2003) show in their research that certain changes in learning and memory may occur through the steroid hormones inducing the alteration of AMPA and NMDA receptor densities, particularly in the glutamatergic intrahippocampal pathway. During estrus and diestrus periods in adult rats of both sexes, steroid hormones appear to affect the densities of AMPA and NMDA receptors in the hippocampus. These receptor types are both crucial for LTP: AMPA receptors depolarize the post-synaptic cell, and NMDA receptors allow the induction of LTP (Rudy, 2007). The location of these receptors in the hippocampus is also important, as the hippocampus plays a major role in memory. Bidmon et al. conducted research on in vivo steroid hormone impact on the density of these receptors in adult rats. They found that the density of AMPA receptors are significantly reduced in hippocampal regions of the female rats in estrus, when compared to females in diestrus; although there were differences in NMDA receptors, they were not significant. They also found ovariectomy to be associated with stress, and that overiectomized rats show changes in plasma levels of glucocorticoids and mineralocorticoids due to altered activity of the adrenal cortex. In these ovariectomized rats, it is the upregulation of NMDA receptor densities that is described as being sensitive to changing hormonal levels. These results show that an increase of glucocorticoids and mineralocorticoids in the blood has an affect on the density of NMDA receptors. NMDA receptors have been implicated in LTP; based on these results, it can be hypothesized that an increase in stress (hormonally) is condusive to learning (based on an increase in receptor density).
The binding sites of the steroid hormones have also shown to play a role in learning and memory. The adrenal steroid hormones bind to glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the hippocampus, and modulate stress responses. The hippocampus as been implicated in spatial memory, and as such it can be hypothesized that there is a relationship between stress hormones and memory.
Akirav et al. (2004) found that high doses of stress induced before training or testing led to an impairment in spatial performance and memory. This study showed that rats that performed well in a spatial task in cold water, which induced moderate stress, deteriorated following the suppression of corticosterone levels. Rats trained in warm water, inducing mild stress, who did not perform as well, on average, as the cold water-trained animals, improved following the rise in corticosterone levels. The relationship between the particular level of stress is important, as high levels hormones have been shown to have a positive effect on spatial memory, whereas moderate levels appear to be less effective.
An imbalance between the GRs and the MRs is thought to play a role in stress-related disorders; stress-related disorders may be attributed to learned stress. Using a fear conditioning experiment, Berger et al. (2009) showed that upregulation of GRs most likely contributes to the consolidation of fear behaviour. They tested mice with forebrain ablations of MRs in various behavioural tasks, including fear conditioning. This examines the adaptive effects of steroid hormone receptors on behaviour, as the relationship between stress and memory is important for learning about danger. Because MR has been shown to “mediate the regulation of basal corticosterone levels and the initial corticosterone secretion during the ultradian rhythm and after stress” (Berger, 2009) and GR has been attributed to consolidation of such memories, Berger et al. hypothesize a relationship between the function of the MRs and the GRs. MRCaMKCre mice showed enhanced fear during acquisition of the task, suggesting that the two receptor types work in a way which is complementary to one another. The MRs have a much greater affinity for the hormones, which could be useful with regards to the MRs being involved in the early acquisition of the memory. The results of Berger et al. show that after 4 days of training, the MRCaMKCre mice have a 40% higher concentration of corticosterone than the control group, showing the connection between learning and corticosterone.
The dentate gyrus of the hippocampus is particularly important, as Krugers et al. (2007) describe in the results of their study on the timing of hormone application in the dentate gyrus and the effects of timing on LTP.
They tested both rapid and delayed corticosterone activity on B-adrenergic-dependent changes in LTP. Their results show that the B-adrenergic agonist isoproterenol, when applied concurrently with corticosterone, enhanced synaptic strength, but when corticosterone was given in advance of isoproterenol, no potentiation was shown. These results describe timing-dependent nature of the synaptic plasticity involved in LTP, in relation to activity of the stress hormone corticosterone. In terms of behaviour, this is to say that stress enhances learning when the two occur close in time. The adaptive function of a such a system is that it “may promote encoding of the information associated with the stressful event” (Krugers, 2007).
The retrieval of memories can be disrupted by lesions or malfunction in the areas of the brain associated with learning. Beracochea et al. (2009) lesioned the mediodorsal thalamus, associated with diencephalic amnesia and found that it blocked stress-induced inversion of the serial memory retrieval in mice. These results are much like those observed in prior studies done regarding prefrontal cortex or amygdala-lesioned mice. Beracochea's 2009 study proposes a circuit which comprises these 3 structures to thus be involved in serial memory retrieval. “Long lasting synaptic changes have been observed in the thalamo-amygdala and thalamo-prefrontal pathways following associative emotional memory” (Beracochea, 2009), which would be related to activation of the amygdala. The activation of the amygdala in this experiment was also shown to suppress hippocampal plasticity. Beracochea et al. hypothesize that this is the result of a shift of strategy under certain conditions. They give several reasons why lesioning the mediodorsal thalamus may suppress stress-induced serial memory retrieval, one being that removal of this region eliminates a large portion of excitatory glutamatergic activity coming from the prefrontal cortex. This may cause a reduction in synaptic activity and thus a reduction in LTP.
The studies presented in this discussion on hormonal effects on learning reflect the current research being done in this field. There is a focus in current research on understanding the effects of steroid hormones on neural plasticity, such as that which occurs in LTP. It would be beneficial for future research to study the involvement of the processes which stimulate hormonal release, due to the time-dependency of the relationship between hormones and learning. Perhaps the mechanisms leading to hormonal secretion occur differently when in relation to learning, allowing faster activity of the hormone. Another area of study which could be useful would be to understand the connection between the different affinities of the two hormone receptor types (MRs and GRs), and their respective roles in memory acquisition and consolidation. This might lead to a greater understanding of the ways in which acquisition and consolidation differ on a molecular level. It would also be beneficial for future research to examine the effects of other types of hormones on learning, as most of the research appears to be concentrated on the stress hormones and the involvement of the H-P-A axis. Due to the interrelated nature of the endocrine system and the neural networks, it is probable that other hormones may have an influence learning and memory as well.
References
Akirav, I., Kozenicky, M., Richter-Levin, G., Sandi, C., Tal, D., Venero, C. (2004). A Facilitative Role for Corticosterone in the Acquisition of a Spatial Task Under Moderate Stress. Learning and Memory, 11, 188-195.
Beracochea, D., Celerier, A., Chauveau, F., Christophe, T., Guillou, J. L., Pierard, C., Vouimba, R. M. (2009). Mediodorsal thalamic lesions block the stress-induced inversion of serial memory retrieval pattern in mice. Behavioural Brain Research, 203, 270-278.
Berger, S., Brinks, V., Gass, P., de Kloet, E. R., Oitzl, M. S. (2009). Mineralocorticoid receptors in control of emotional arousal and fear memory. Hormones and Behaviour, 56, 232-238.
Bidmon, H., Palomero-Gallagher, N., Zilles, C. (2003). AMPA, Kainate, and NMDA Receptor Densities in the Hippocampus of Untreated Male Rats and Females in Estrus and Diestrus. The Journal of Comparative Neurology, 459, 468-474.
Brown, R. E. (1994). An Introduction to Neuroendocrinology. New York: Cambridge University Press.
Bulmer, S., Carlile, J., Corcoran, C., Ferrier, I. N., Gallagher, F. P., Horton, K., Watson, S. (2009). Effect of aspirin on hypothalamic–pituitary–adrenal function and on neuropsychological performance in healthy adults: a pilot study. Psychopharmacology, 205, 151-155.
Krugers, H. J., Joels, M., Pu, Z. (2007). Corticosterone time-dependently modulates B-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus. Learning and Memory, 14,359-367.
Rudy, J. (2007) Neurobiology of Learning and Memory, Chapters 1-4.
It also may be attributed to hormone receptors in circuits and areas of the brain that are specifically associated with learning and memory. The particular amount of the hormone is crucial: high levels of stress can be condusive to learning, but low levels of stress has shown to be detrimental. Further proving this relationship, the lesioning of areas associated with learning in ablation studies of mice blocks the stress-induced inversion of serial memory retrieval.
The steroid hormones of the adrenal cortex (the glucocorticoids and the mineralocorticoids) have been implicated in learning and memory. The glucocorticoids include cortisol and corticosterone, among others; what the glucocorticoids do is modulate carbohydrate metabolism by converting stored proteins into carbohydrates (Brown, 1994). Glucocorticoids (corticosteroids in rats) are released in response to stressful stimuli, and this response has been shown to have an effect on learning and memory. The hypothalamus produces corticotropin releasing hormone (CRH), which in turn stimulates adrenocorticotropic hormone (ACTH) release. ACTH is a pituitary hormone of the pars distalis, which then stimulates glucocorticoid release from the adrenal cortex. It is produced in the corticotroph cells of the adenohypophysis. Because of the three structures involved, these hormones are said to operate in a third-order feedback loop known as the hypothalamic-pituitary-adrenal (H-P-A) axis (Brown, 1994).
As shown by Akirav et al. (2004), the activation of this system causes emotionally charged experiences to alter memory storage. Glucocorticoids and mineralocorticoids bind to receptors in areas of the forebrain which play a role in emotional regulation, learning and memory processes (Berger, 2009). These receptors also “act as transcription factors and mediate complementary but also in part overlapping actions of corticosterone in endocrine and behavioural functions” (Berger, 2009). The effects of these the steroid hormones on LTP is presumed to be time-dependent; previous experiments in the hippocampal CA1 area describe the glucocorticoid corticosterone's facilitation of long-term potentiation in a rapid non-genomic fashion. This same hormone suppresses LTP that is induced several hours after the hormone's application (Krugers, 2007).
Bidmon et al. (2003) show in their research that certain changes in learning and memory may occur through the steroid hormones inducing the alteration of AMPA and NMDA receptor densities, particularly in the glutamatergic intrahippocampal pathway. During estrus and diestrus periods in adult rats of both sexes, steroid hormones appear to affect the densities of AMPA and NMDA receptors in the hippocampus. These receptor types are both crucial for LTP: AMPA receptors depolarize the post-synaptic cell, and NMDA receptors allow the induction of LTP (Rudy, 2007). The location of these receptors in the hippocampus is also important, as the hippocampus plays a major role in memory. Bidmon et al. conducted research on in vivo steroid hormone impact on the density of these receptors in adult rats. They found that the density of AMPA receptors are significantly reduced in hippocampal regions of the female rats in estrus, when compared to females in diestrus; although there were differences in NMDA receptors, they were not significant. They also found ovariectomy to be associated with stress, and that overiectomized rats show changes in plasma levels of glucocorticoids and mineralocorticoids due to altered activity of the adrenal cortex. In these ovariectomized rats, it is the upregulation of NMDA receptor densities that is described as being sensitive to changing hormonal levels. These results show that an increase of glucocorticoids and mineralocorticoids in the blood has an affect on the density of NMDA receptors. NMDA receptors have been implicated in LTP; based on these results, it can be hypothesized that an increase in stress (hormonally) is condusive to learning (based on an increase in receptor density).
The binding sites of the steroid hormones have also shown to play a role in learning and memory. The adrenal steroid hormones bind to glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) in the hippocampus, and modulate stress responses. The hippocampus as been implicated in spatial memory, and as such it can be hypothesized that there is a relationship between stress hormones and memory.
Akirav et al. (2004) found that high doses of stress induced before training or testing led to an impairment in spatial performance and memory. This study showed that rats that performed well in a spatial task in cold water, which induced moderate stress, deteriorated following the suppression of corticosterone levels. Rats trained in warm water, inducing mild stress, who did not perform as well, on average, as the cold water-trained animals, improved following the rise in corticosterone levels. The relationship between the particular level of stress is important, as high levels hormones have been shown to have a positive effect on spatial memory, whereas moderate levels appear to be less effective.
An imbalance between the GRs and the MRs is thought to play a role in stress-related disorders; stress-related disorders may be attributed to learned stress. Using a fear conditioning experiment, Berger et al. (2009) showed that upregulation of GRs most likely contributes to the consolidation of fear behaviour. They tested mice with forebrain ablations of MRs in various behavioural tasks, including fear conditioning. This examines the adaptive effects of steroid hormone receptors on behaviour, as the relationship between stress and memory is important for learning about danger. Because MR has been shown to “mediate the regulation of basal corticosterone levels and the initial corticosterone secretion during the ultradian rhythm and after stress” (Berger, 2009) and GR has been attributed to consolidation of such memories, Berger et al. hypothesize a relationship between the function of the MRs and the GRs. MRCaMKCre mice showed enhanced fear during acquisition of the task, suggesting that the two receptor types work in a way which is complementary to one another. The MRs have a much greater affinity for the hormones, which could be useful with regards to the MRs being involved in the early acquisition of the memory. The results of Berger et al. show that after 4 days of training, the MRCaMKCre mice have a 40% higher concentration of corticosterone than the control group, showing the connection between learning and corticosterone.
The dentate gyrus of the hippocampus is particularly important, as Krugers et al. (2007) describe in the results of their study on the timing of hormone application in the dentate gyrus and the effects of timing on LTP.
They tested both rapid and delayed corticosterone activity on B-adrenergic-dependent changes in LTP. Their results show that the B-adrenergic agonist isoproterenol, when applied concurrently with corticosterone, enhanced synaptic strength, but when corticosterone was given in advance of isoproterenol, no potentiation was shown. These results describe timing-dependent nature of the synaptic plasticity involved in LTP, in relation to activity of the stress hormone corticosterone. In terms of behaviour, this is to say that stress enhances learning when the two occur close in time. The adaptive function of a such a system is that it “may promote encoding of the information associated with the stressful event” (Krugers, 2007).
The retrieval of memories can be disrupted by lesions or malfunction in the areas of the brain associated with learning. Beracochea et al. (2009) lesioned the mediodorsal thalamus, associated with diencephalic amnesia and found that it blocked stress-induced inversion of the serial memory retrieval in mice. These results are much like those observed in prior studies done regarding prefrontal cortex or amygdala-lesioned mice. Beracochea's 2009 study proposes a circuit which comprises these 3 structures to thus be involved in serial memory retrieval. “Long lasting synaptic changes have been observed in the thalamo-amygdala and thalamo-prefrontal pathways following associative emotional memory” (Beracochea, 2009), which would be related to activation of the amygdala. The activation of the amygdala in this experiment was also shown to suppress hippocampal plasticity. Beracochea et al. hypothesize that this is the result of a shift of strategy under certain conditions. They give several reasons why lesioning the mediodorsal thalamus may suppress stress-induced serial memory retrieval, one being that removal of this region eliminates a large portion of excitatory glutamatergic activity coming from the prefrontal cortex. This may cause a reduction in synaptic activity and thus a reduction in LTP.
The studies presented in this discussion on hormonal effects on learning reflect the current research being done in this field. There is a focus in current research on understanding the effects of steroid hormones on neural plasticity, such as that which occurs in LTP. It would be beneficial for future research to study the involvement of the processes which stimulate hormonal release, due to the time-dependency of the relationship between hormones and learning. Perhaps the mechanisms leading to hormonal secretion occur differently when in relation to learning, allowing faster activity of the hormone. Another area of study which could be useful would be to understand the connection between the different affinities of the two hormone receptor types (MRs and GRs), and their respective roles in memory acquisition and consolidation. This might lead to a greater understanding of the ways in which acquisition and consolidation differ on a molecular level. It would also be beneficial for future research to examine the effects of other types of hormones on learning, as most of the research appears to be concentrated on the stress hormones and the involvement of the H-P-A axis. Due to the interrelated nature of the endocrine system and the neural networks, it is probable that other hormones may have an influence learning and memory as well.
References
Akirav, I., Kozenicky, M., Richter-Levin, G., Sandi, C., Tal, D., Venero, C. (2004). A Facilitative Role for Corticosterone in the Acquisition of a Spatial Task Under Moderate Stress. Learning and Memory, 11, 188-195.
Beracochea, D., Celerier, A., Chauveau, F., Christophe, T., Guillou, J. L., Pierard, C., Vouimba, R. M. (2009). Mediodorsal thalamic lesions block the stress-induced inversion of serial memory retrieval pattern in mice. Behavioural Brain Research, 203, 270-278.
Berger, S., Brinks, V., Gass, P., de Kloet, E. R., Oitzl, M. S. (2009). Mineralocorticoid receptors in control of emotional arousal and fear memory. Hormones and Behaviour, 56, 232-238.
Bidmon, H., Palomero-Gallagher, N., Zilles, C. (2003). AMPA, Kainate, and NMDA Receptor Densities in the Hippocampus of Untreated Male Rats and Females in Estrus and Diestrus. The Journal of Comparative Neurology, 459, 468-474.
Brown, R. E. (1994). An Introduction to Neuroendocrinology. New York: Cambridge University Press.
Bulmer, S., Carlile, J., Corcoran, C., Ferrier, I. N., Gallagher, F. P., Horton, K., Watson, S. (2009). Effect of aspirin on hypothalamic–pituitary–adrenal function and on neuropsychological performance in healthy adults: a pilot study. Psychopharmacology, 205, 151-155.
Krugers, H. J., Joels, M., Pu, Z. (2007). Corticosterone time-dependently modulates B-adrenergic effects on long-term potentiation in the hippocampal dentate gyrus. Learning and Memory, 14,359-367.
Rudy, J. (2007) Neurobiology of Learning and Memory, Chapters 1-4.
Sunday, February 14, 2010
The Mystery of the Cochlear Frequency Tuning Curve
In the later 1940s, Hungarian physiologist Georg von Bekesy was perturbed by a commonly held belief regarding the perception of hearing. A long standing analogy that compared the basilar membrane (on which rests the organ of Corti, which allows us to transduce sound through hair cells) of the cochlea to a wave travelling down a skipping rope just didn’t seem right to him. He decided that it was time for him to go into the cochlea- surgically- and figure the whole mess out.
Von Bekesy transected the basilar membrane, separating the base from the apex, and found that it did not alter frequency perception in the slightest! So von Bekesy hypothesized that the waves would be in the fluid. The cochlea is, after all, filled with a fluid called endolymph (which is very similar to intracellular fluid).
But then what of the place code? For von Bekesy was certain (though it had not been proven) that for each frequency in an auditory stimulus, there was a unique place on the basilar membrane. He decided to do what any inquisitive mind must: he examined it underneath a microscope. And although he could only use low frequency stimuli (because high frequencies are so high that our eyes cannot perceive them), he found that certain places on the basilar membrane vibrate better at some frequencies than at others.
From this he drew a frequency tuning curve:
If you were to choose a different place on the basilar membrane and measure a different frequency, the curve will be the very same shape, but with the most sensitive point in a different place.
Then physiologist Bill Rhode had a very clever idea: to use the nuclear physics Mossbauer technique to measure frequency along the entire basilar membrane. The technique is done as follows: first, a tiny piece of palladium foil (which is very similar to aluminum foil) is soaked in radioactive cobalt. Next, the cochlea is gently opened and the foil is floated (from the bottom, to avoid the organ of Corti) onto the basilar membrane. The radioactive cobalt then emits gamma rays at such an incredibly high frequency that they are actually out of our acoustic range, but are still measurable. Finally, something else in the cochlea but be in the cochlea to will measure the gamma rays. If the basilar membrane (and the palladium foil) move up, the wavelengths of the gamma rays get squeezed in; or down, and pulled away (see: Doppler effect). This squeezing and stretching allows very accurate measurement of basilar membrane movement, with several benefits, the most important being that this can be done in a live animal. Using this technique, Rhode was able to determine the specific frequencies of the place code along the basilar membrane.
But in a seemingly unfortunate turn of events, the animal which was being used for this test died. Rhode would not let this stop him. He decided to perform the very same test, but this time on the deceased animal. The results produced a very strange frequency tuning curve indeed:
It looked just like the curve produced by von Bekesy in the removed cochlea seen under the microscope! Rhode decided to plot the results from the animal’s live cochlea on the same type of curve, which brings us to one of the greatest mysteries in psychoacoustic history, for the frequency tuning curve looked like this:
The curve produced from the cochlea of the dead animal (which from hereon in will be referred to as the passive curve) is but exactly what one would have expected the curve to look like (especially after the discoveries of von Bekesy). However the curve from the live animal (the active curve) is simply impossible! The basilar membrane does not have the physical capability to produce such a curve; it is far more selective (look at how low it dips) and sensitive (look at how skinny it is) than it should be...
But along came 5 experiments that explained the whole thing, done separately by Bob Harrison, Alan Cody, Weiderhold, Mario Ruggero and Charlie Liberman. Their work ultimately uncovered the truth behind the mystery of the basilar membrane and why it is that the active and passive frequency tuning curves are so vastly different. So here is how it works:
First, the stapes pushes on the oval window (following a succession of impedance mismatch solutions), in the middle ear.
This sets the fluid in the cochlea (the endolymph) into motion. The motion of the endolymph causes the hair cells to move. The outer hair cells are anchored to both the basilar membrane and the tectorial membrane, and move in a contractile way as a result of metabolic energy from a protein called prestin. The amplitude of this contracted response is equal to the membrane potential: the outer hair cells create the mechanical signal in auditory transduction.
The combination of fluid movement and outer hair cell contraction causes movement of the basilar membrane, which then also moves the inner hair cells: they are the passive transducers.
And so, we now know that Rhode’s results on the passive frequency tuning curve were as a result of a lack of metabolic activity (as in von Bekesy’s)in the outer hair cells; metabolic activity does not occur in death.
The basilar membrane is not physically capable of producing the active frequency tuning curve- not without the help of the outer hair cells, that is.
Von Bekesy transected the basilar membrane, separating the base from the apex, and found that it did not alter frequency perception in the slightest! So von Bekesy hypothesized that the waves would be in the fluid. The cochlea is, after all, filled with a fluid called endolymph (which is very similar to intracellular fluid).
But then what of the place code? For von Bekesy was certain (though it had not been proven) that for each frequency in an auditory stimulus, there was a unique place on the basilar membrane. He decided to do what any inquisitive mind must: he examined it underneath a microscope. And although he could only use low frequency stimuli (because high frequencies are so high that our eyes cannot perceive them), he found that certain places on the basilar membrane vibrate better at some frequencies than at others.
From this he drew a frequency tuning curve:
If you were to choose a different place on the basilar membrane and measure a different frequency, the curve will be the very same shape, but with the most sensitive point in a different place.
Then physiologist Bill Rhode had a very clever idea: to use the nuclear physics Mossbauer technique to measure frequency along the entire basilar membrane. The technique is done as follows: first, a tiny piece of palladium foil (which is very similar to aluminum foil) is soaked in radioactive cobalt. Next, the cochlea is gently opened and the foil is floated (from the bottom, to avoid the organ of Corti) onto the basilar membrane. The radioactive cobalt then emits gamma rays at such an incredibly high frequency that they are actually out of our acoustic range, but are still measurable. Finally, something else in the cochlea but be in the cochlea to will measure the gamma rays. If the basilar membrane (and the palladium foil) move up, the wavelengths of the gamma rays get squeezed in; or down, and pulled away (see: Doppler effect). This squeezing and stretching allows very accurate measurement of basilar membrane movement, with several benefits, the most important being that this can be done in a live animal. Using this technique, Rhode was able to determine the specific frequencies of the place code along the basilar membrane.
But in a seemingly unfortunate turn of events, the animal which was being used for this test died. Rhode would not let this stop him. He decided to perform the very same test, but this time on the deceased animal. The results produced a very strange frequency tuning curve indeed:
It looked just like the curve produced by von Bekesy in the removed cochlea seen under the microscope! Rhode decided to plot the results from the animal’s live cochlea on the same type of curve, which brings us to one of the greatest mysteries in psychoacoustic history, for the frequency tuning curve looked like this:
The curve produced from the cochlea of the dead animal (which from hereon in will be referred to as the passive curve) is but exactly what one would have expected the curve to look like (especially after the discoveries of von Bekesy). However the curve from the live animal (the active curve) is simply impossible! The basilar membrane does not have the physical capability to produce such a curve; it is far more selective (look at how low it dips) and sensitive (look at how skinny it is) than it should be...
But along came 5 experiments that explained the whole thing, done separately by Bob Harrison, Alan Cody, Weiderhold, Mario Ruggero and Charlie Liberman. Their work ultimately uncovered the truth behind the mystery of the basilar membrane and why it is that the active and passive frequency tuning curves are so vastly different. So here is how it works:
First, the stapes pushes on the oval window (following a succession of impedance mismatch solutions), in the middle ear.
This sets the fluid in the cochlea (the endolymph) into motion. The motion of the endolymph causes the hair cells to move. The outer hair cells are anchored to both the basilar membrane and the tectorial membrane, and move in a contractile way as a result of metabolic energy from a protein called prestin. The amplitude of this contracted response is equal to the membrane potential: the outer hair cells create the mechanical signal in auditory transduction.
The combination of fluid movement and outer hair cell contraction causes movement of the basilar membrane, which then also moves the inner hair cells: they are the passive transducers.
And so, we now know that Rhode’s results on the passive frequency tuning curve were as a result of a lack of metabolic activity (as in von Bekesy’s)in the outer hair cells; metabolic activity does not occur in death.
The basilar membrane is not physically capable of producing the active frequency tuning curve- not without the help of the outer hair cells, that is.
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