Forgetting throughout the Ages - From Infancy to Old Age

The phenomenon of forgetting remains relevant from birth to old age. The causes of forgetting may be attributed to chemicals, injury, age-related factors, or abnormal development. In some cases, memory loss is beneficial and is required for normal cognitive function; however, in other instances, it can be damaging and destructive. Forgetting involves interference of explicit memories at any of the three stages of memory: encoding, consolidation, and recall. Explicit memories refer to memories of events or knowledge and are initially encoded as increased glutamatergic transmission and receptor trafficking at specific synapses in areas such as the hippocampus. The stabilization of a memory trace following acquisition is called consolidation and is characterized by de novo protein synthesis. Consolidation occurs in two stages: synaptic consolidation, which includes structural cellular modifications and long-term potentiation, and systems consolidation, which involves the transfer of memories from the hippocampus to the neocortex. In recall, a memory is subjected to reconsolidation, during which memories are unstable. Reconsolidation requires de novo protein synthesis, cell signaling, and transcription factors such as cyclic-AMP response element binding (CREB) protein[1]. The forgetting we experience daily can be attributed to interference, which may interrupt synaptic consolidation, therefore inhibiting later recall. Interference may also disturb memories during recall due to the increased plasticity in reconsolidation[2]. Abnormal forgetting involves the direct harm or deterioration of cortical structures and cells that are involved in forming or storing memories. The benefits and detriments of memory loss can be assessed through examining its mechanisms in infantile amnesia, traumatic brain injury (TBI), drug-induced forgetting, and Alzheimer’s disease.

1. Tronson, N. C., and Taylor, J. R. (2007). Molecular mechanisms of memory reconsolidation. Nature Reviews Neuroscience, 8(4), 262-275.
2. Hardt, O., Nader, K., & Nadel, L. (2013). Decay happens: the role of active forgetting in memory. Trends in cognitive sciences, 17(3), 111-120.

Alzheimer's Disease and LTP Impairment

main article: Alzheimer's Disease and LTP Impairment
author: Krystal Menezes
Alzheimer's disease (AD), a neurodegenerative disorder, is most well-known for its characteristic symptom of dementia. Other symptoms include loss of reasoning, insight and even a decline in language abilities. There have been many neuromolecular pathologies that have been thought to be implicated in the symptoms associated with AD, which include but are not limited to neurofibrillary tangles that have been thought to be composed of hyperphosphorylated tau protein and Amyloid β plaques that are created through the aggregation of amyloid-B oligomers (Aβ proteins), particularly the spliced version Aβ42, which is the main contributor to the production of these AB diffuse plaques in vivo [1]

The function of AB aggregations in their role with LTP was clarified when it was shown that LTP could be inhibited via injection of AB oligomers into hippocampal slices [2]. Experiments of AB injections in vivo not only showed that the aggregates still inhibited LTP [3], but also showed that the injections led to poor performances by mice in learning paradigm tests [4]. These findings were strengthened through a paper which showed that the injection of an AB aggregation inhibitor, SEN1269 was able to rescue LTP deficits in vitro as well as in vivo [5].
There have been numerous explanations for the molecular mechanism by which AB oligomers are able to inhibit LTP. Rammes et al. 2011 (please see [6] ) have attributed inhibition of LTP to the ability that AB plaques have in inducing excitotoxicity via mGlu5 receptors and excessive NMDA receptor function. Whereas, Selkoe, 2008 ( please see [7] ) attributed LTP inhibition to the reduced synaptic spines due to the reduced intracellular Ca influx which favoured LTD over LTP. Lastly, Vitolo et al., 2002 [8] showed that upon treatment of hippocampal cultured cells with AB there was an increased inhibition of PKA and subsequently, a reduction of CREB phosphorylation and action.

Alzheimer's Disease and Synaptic Dysfunction
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Neuron, Walsh et al. 2004
1. Selkoe, D. J. Alzheimer ’ s Disease : Genes , Proteins , and Therapy. 81, 741–766 (2001).
2. Nomura, I., Takechi, H. & Kato, N. Intraneuronally injected amyloid β inhibits long-term potentiation in rat hippocampal slices. J. Neurophysiol. 107, 2526–31 (2012).
3. Walsh, D. M. et al. Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–9 (2002).
4. Cleary, J. P. et al. Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function. Nat. Neurosci. 8, 79–84 (2005).
5. Scopes, D. I. C. et al. Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity. Br. J. Pharmacol. 167, 383–92 (2012).
6. Rammes, G., Hasenjäger, A., Sroka-Saidi, K., Deussing, J. M. & Parsons, C. G. Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices. Neuropharmacology 60, 982–90 (2011).
7. Selkoe, D. J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior. Behav. Brain Res. 192, 106–13 (2008).
8. Vitolo, O. V et al. Amyloid beta -peptide inhibition of the PKA/CREB pathway and long-term potentiation: reversibility by drugs that enhance cAMP signaling. Proc. Natl. Acad. Sci. U. S. A. 99, 13217–21 (2002).

Drug-Induced Forgetting

main article: Drug-Induced Forgetting
author: Victoria Chuen

A pill to help you forget?
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There are currently no drugs specifically designed for the purpose
of induced-forgetting in humans. Adapted from [Bibliography item pills not found.]

Drug-induced forgetting is a form of memory loss resulting from pharmacological effects and can be regarded as detrimental or beneficial, depending on the intended use of the drug. Many medications are engineered to treat illnesses unrelated to memory, but contain forgetting as a negative side effect. Conversely, for patients undergoing major medical procedures and others who suffer from drug addiction or posttraumatic stress disorder (PTSD), drug-induced forgetting may be regarded as therapeutic. PTSD is an anxiety disorder that affects people worldwide; the potential to erase or weaken the traumatic memory underlying a patient’s diagnosis has powerful implications. Although it is not yet possible to completely erase traumatic memories in humans, it has been successfully modeled in rodents using drugs that manipulate epigenetic changes[1], protein synthesis inhibitors[2], and glucocorticoid receptor antagonists[3]. In attempts to erase memories, a common method is to target the labile period that occurs after recall. During this time period, the previously stable memory is subject to disruption[2], updating or erasure.

1. Gräff, J., Joseph, N. F., Horn, M. E., Samiei, A., Meng, J., Seo, J., … & Tsai, L. H. (2014). Epigenetic Priming of Memory Updating during Reconsolidation to Attenuate Remote Fear Memories. Cell, 156(1), 261-276
2. Nader, K., Schafe, G. E., & Le Doux, J. E. (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature,406(6797), 722-726.
3. Taubenfeld, S. M., Riceberg, J. S., New, A. S., & Alberini, C. M. (2009). Preclinical assessment for selectively disrupting a traumatic memory via postretrieval inhibition of glucocorticoid receptors. Biological psychiatry, 65(3), 249-257.

Infantile Amnesia

main article: Infantile Amnesia
author: Audrey Zhang

Infantile Amnesia
What happens during infantile amnesia?
Adapted from [Bibliography item ref21 not found.]

Infantile amnesia, or childhood amnesia, is a two stage phenomenon, characterized by the near absence of explicit or declarative memory for events that occurred from 2-3 years of age, and spotty memory for events that occurred 3-7 years of age. Forgetting cannot simply be attributed to normal forgetting, as the number of memories that can be recalled as an adult for events that took place during infancy is below what would be expected by extrapolating the adult forgetting curve. Although the neural mechanisms underlying infantile amnesia are still debated, there are many early cognitive and psychological theories, and recent biological theories that attempt to account for the phenomenon. These biological theories generally fall into two categories – one that dictates that brain regions responsible for episodic memory are still immature, and the other that says the ongoing postnatal neurogenesis interferes with the ability to form and consolidate stable memories [1]. Recent research has also shown that the development of infantile amnesia can be alleviated by administering pharmacological agents post-training in rat models (such as epinephrine, norepinephrine, glucose, GABA, and naloxone) [2]. Further research in infantile amnesia shows that it has an important implication in the treatment of anxiety disorders.

1. Josselyn, S. A., & Frankland, P. W. (2012). Infantile amnesia: a neurogenic hypothesis. Learning & Memory, 19(9), 423-433.
2. Weber, M., McNally, G. P., & Richardson, R. (2006). Opioid receptors regulate retrieval of infant fear memories: Effects of naloxone on infantile amnesia. Behavioral neuroscience, 120(3), 702.

Traumatic Brain Injury and Forgetting

main article: Traumatic Brain Injury and Forgetting
author: Meena Sundararaj

Accidents Can be Serious
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Take care to wear a helmet. [Bibliography item dreamstime not found.] (2014)

Traumatic Brain Injury (TBI) is caused by physical trauma to the head or neck and can lead to disruptions in memory, learning, cognitive abilities, sleep, and mood. Many brain areas may be damaged in TBI, commonly the frontal cortex and the temporal lobes. In the immediate or primary stage of injury, cells and blood vessels are ripped or contorted. During secondary injury, which takes place in the weeks and months following impact, the brain shows diffuse inflammation and neurotoxin release as well as breakage of the blood brain barrier. Axons of cells throughout the brain may detach from cell bodies. Within cells, mitochondria function defectively, and there are inappropriate amounts of glutamate release and cation entry [1]. Individuals with more severe TBI may show high concentrations of amyloid-beta plaques and neurofibrillary tangles, factors associated with dementia [2]. All of these changes can cause forgetting if they damage memory structures such as the hippocampus, where memories are formed, and the cortex, in which memories are consolidated. Memory loss can be temporary, or in other cases, can manifest as anterograde or retrograde amnesia. Current treatments for TBI in humans are mostly rehabilitation services. Recently, much research is looking at potential drugs and compounds that can treat the pathology that follows injury.

1. Giustini, A., Pistarini, C., Pisoni, C. (2013). Traumatic and nontraumatic brain injury. Neurological Rehabilitation: Handbook of Clinical Neurology. 110: 401-409.
2. Corrigan, J. D., Hammond, F. M. (2013). Traumatic Brain Injury as a Chronic Health Condition. Archives of Physical Medicine and Rehabilitation. 94(6): 1199-1201.

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