As compounds are optimized by our ROP criteria, we will progress lead compounds towards in vivo efficacy studies, which will be in three well-established and well-accepted mouse models for memory storage. These three tests capture various forms of memory (working memory, object recognition memory and fear memory) in mice and have translational validity for human drug screening for memory disorders. Based on the published data from our lab and others (Ref) our working hypothesis is that positive compounds will enhance memory storage. The following preliminary results support the feasibility of this aim.
C5A.1. Regulation of specific kinesins in mouse hippocampus during contextual fear memory storage: We have studied whether levels of specific kinesins change during memory formation. We selected 6 kinesin genes from the hippocampus (HPC) and carried out qRT-PCR analysis of RNAs from HPC (N=4 biological replications) isolated one hour after contextual fear conditioning (CFC) training, during the initial consolidation of the long-term memory. We identified KIf5B to be significantly upregulated (~1.7 fold, N=4; Students t test, p<0.005) in the HPC following CFC training (Fig ).
C5A.2. Stereotaxic surgeries and delivery of compounds to specific regions of mouse brain. These studies are ongoing in the Puthanveettil lab (Figure XX). An example of such study is shown in Figure XX, where we injected a lentiviral vector to express eGFP in CA1 sub-region of the mouse hippocampus.
As a human get older, many of the organs will deteriorate and lost the functions. Out of all of the organs, our brains are extremely vulnerable to the process of aging. In the article of “Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice”, the researchers leaded by Saul Villeda in University of California, San Francisco, focus on the study of physical and functional property of the hippocampus in mice. Hippocampus manages the learning and memory process. However, it is extremely sensitive to aging and shows many down regulations as the brain ages. The study had also revealed the important role of Creb, which maintain hippocampus properly functional and healthy. Two different assays were used to study the role of Creb in the cognitive function and synaptic plasticity which includes testing hippocampus-related memorizing and learning processes and measuring the dendritic spine number and synaptic plasticity.
Among these different processes are encoding, storage, consolidation, and retrieval. This study hypothesized that the hippocampus plays a different role in each of these. The method of this study is especially unique because it used temporary chemical inactivation of the hippocampus, which had not been done before. This temporary inactivation is unique because it lets the researchers selectively assess the role of the hippocampus during each of the processes discussed above. To test encoding, the inactivation occurred during learning of a maze task; to test retrieval, inactivation occurred during a retention task. Results indicate the temporary inactivation of the hippocampus impairs both encoding and retrieval. To test long-term consolidation, rats were trained and then separate groups received hippocampal treatment for different amounts of time between one and five days. Results showed that temporary inactivation during this time period disrupts memory for the already learned task. This study partially supports the result of the study by Eldridge et al. (2000) in that they both show the hippocampus is necessary for memory retrieval. However, it does not address the retrieval of different types of memory. This study also supports the idea from Wang et al. (2012) that the hippocampus may be involved in consolidation and storage of new memories but not necessarily of older
The formation of new memories requires protein synthesis dependent changes in synaptic structure and plasticity in the hippocampus. Studies in humans and animals suggest that these memories are initially stored in hippocampus but later transferred to cortex for permanent storage. This phenomenon is described as systems consolidation of memories. While the specific role for new protein synthesis in hippocampus in early encoding of memories is established, whether protein synthesis in medial prefrontal cortex play a major role in encoding of memories is unclear. To address this question, we used contextual fear conditioning (CFC) of mouse, a behavior training that induce long lasting memories. A single training session produces robust lifelong memory (8) that can be measured using automated procedures (9). Several studies have used CFC training as a model to study hippocampal-cortical communications and mechanisms underlying systems consolidation of memories. Contextual fear memories are initially stored in hippocampus and then moved to medial prefrontal cortex (mPFC) for long-term storage.
C. APPROACH: Based on our preliminary data on lncRNA changes in specific regions of the brain associated with contextual fear, we hypothesize that specific lncRNAs mediate consolidation and extinction of fear memories. To test this hypothesis, the Puthanveettil and Stackman laboratories will bring together their strong expertise in genomics, bioinformatics, noncoding RNAs, genetics, behavioral models, non-coding RNAs, bioinformatics and functional, in vivo manipulations of novel molecular players. We will employ a research strategy that starts with an unbiased, genome-wide analysis of lncRNAs and funnel down to key players, at which point mechanisms of action will be identified. First, unbiased expression analysis of lncRNAs will be carried out with contextual fear conditioning following extinction of contextual fear memory. Second, we will then carry out in vivo manipulation of specific lncRNAs in specific regions of the brain to determine necessity of the expression of specific lncRNAs in consolidation and extinction of fear memory. We anticipate that our studies will establish the functional importance of candidate lncRNAs in consolidation and extinction and provide novel insights into the novel molecular regulators and mechanisms underlying development of PTSDs. All of the genomics, bioinformatics and rodent behavior analyses will be carried out locally, at Scripps Florida and FAU, with confocal imaging experiments being performed across the street at the Max Planck
We have discovered that contextual fear memories, reliant on synaptic plasticity, altered the expression of specific lncRNAs in two regions of the mouse brain implicated in PTSD, the medial prefrontal cortex (mPFC), and CA1 sub-region of hippocampus. Among the nine lncRNAs we measured, one (GM11549) was upregulated in mPFC and two lncRNAs are regulated in CA1. Our working hypothesis is that the consolidation of contextual fear memory is dependent upon a subset of lncRNAs within the circuit governing fear memories. To test this hypothesis, we will focus on the CA1 region of hippocampus that is critically involved in memory consolidation. We will employ two relevant behavioral model, contextual fear conditioning to achieve the following: (1) Identify specific changes in lncRNAs transcriptome profiles in the CA1 by RNAseq analyses at 30 min, 1 and 6 hrs after training and validate specific changes in lncRNAs by quantitative PCR and confocal imaging. (2) Assess the ability of in vivo intra-CA1 manipulations of specific lncRNAs identified by RNAseq to interfere with the consolidation of fear memory. For these functional studies, we will select the top five lncRNAs based on a fold change of >1.5 (p<0.05) and their sequence homology to humans. (3) Elucidate the mechanism(s) of action of the lncRNAs in the consolidation of fear memory. We anticipate that these studies
There is evidence from one study that these drugs can increase cognitive abilities, but there have been no conclusive studies that examined the negative side-effects of these drugs when used for non-medical reasons (Lucke, Bell, Partridge, and Hall par. 10). This suggests that neuroenhancing drugs could be used for the betterment of society. If effective, these drugs have the potential to increase efficiency in
Since hippocampus plays an important function in the brain, it has become a great topic for many conducted research not only on human but also animals, specifically primates and rodents. In primate model of amnesia, the experiment is performed through three main tasks – delayed nonmatch to sample, object discrimination paradigm and motor skill learning across multiple trials (Eichenbaum et al, 1992). In delayed non-matching test, both amnesic and intact monkey show nearly same performance rate in remembering objects across delayed in short period of time (Eichenbaum et al, 1992). In contrast, amnesic monkeys show a great impairment for longer delayed conditions, hours, in picking the right non-matched samples (Eichenbaum et al, 1992). Likewise, in object discrimination task, amnesic monkeys are unable to recognize objects, as compared to control monkeys (Eichenbaum et al, 1992).These tests suggest the importance of hippocampus in acquisition of new information and recollection old events from episodic memory. Additionally, hippocampus also contributes largely to relational representation, as a characteristic of declarative memory (Eichenbaum et al, 1992). This can be shown through odor discrimination and place
The animals were subjected to a battery of behavioral tests during 3-5, 9-11, and 13-15 weeks following icv injection. The behavioral studies included Accelerating Rotarod, Y Maze, and novel object recognition task (NORT) accompanying with Morris water maze. All observations were performed between 10.00 am and 16.00 pm. Equipment was cleaned with 70% ethanol between each test to eliminate olfactory cues. After every test battery, ten animals from each group were sacrificed by decapitation, (Fig.1.), and their brains were removed quickly. Five brains were kept in 4% paraformaldehyde for 24 hours and were then paraffin-embedded for histological studies on the hippocampus (hematoxylin and eosin and cong-red staining). The hippocampi of the other brains were dissected and stored in -70°C for Real-time RT-PCR quantification of insulin receptor (IR), tau and choline acetyltransferase
Cognition enhancing drugs has become very popular in recent decades. As the whole world is facing a problem of population aging, cognitive declining or impairment which can be in parallel with age trend has drawn worldwide attention from neuroscience researchers and pharmaceutical industry. Cognitive difficulties can not only be seen in age-related neurodegenerative diseases like Alzheimer’s disease, but also be caused by some other factors, such as genetic factor or brain injury. Mostly, these diseases or sequelae cannot be cured, reversed or even stopped. To improve life quality of the patients who suffered these diseases, cognition enhancing drugs have been developed as a potential treatment and widely used. Interestingly, more and more
In Carolyn Gregor’s magazine article “8 Fascinating Things We Learned About The Mind in 2015”, she wrote about different people’s chemical abuse , personal lifestyles and environmental choices can affect how the mind reacts to inner workings. Studies found from Script Research Institute may have discovered a new drug which could influence the addiction associated memories in people who are user of meth and other mind altering drugs. This drug will be absorbed into the brain and eventually dissolve past memories which are triggered drug use.
After the successful synthesis, studies on Piracetam were done from all around the world to focus on specific aspects such as to improve memories and the neuroprotection on patients with the Alzheimer’s disease. These studies expanded to other racetams such as Aniracetam and Oxiracetam. Aniracetam was developed by Hoffman-La Roche in 1970’s which contributes to the neurotransmission by activating the Acetylcholine receptors. Oxiracetam was developed in 1993. Its main goal is to improve the capacity to process information. Racetams were revolutionary because there are no side effects and they combine both physiological and medical
Over the years, many researchers have speculated that the cognitive decline experienced in AD patients is due to the loss of acetylcholine (ACh) in the brain (Lane, 2006). The importance of Ach in the brain is well supported in the literature as being essential for memory consolidation and learning. Over the years, researchers have worked diligently in order to increase the levels of ACh and three drugs have been developed and classified as treatment for increasing ACh in AD patients: Galantamine, Donepezil and Rivastigmine (Birks, 2006). In 2000, Wilcock et al implemented a randomized, double blind, placebo controlled trial evaluating the safety and effect of galantamine in treatment of
Global CaMKKβ-/- mice generated by Peters et al were found to have male specific impaired spatial memory formation secondary to reduced spatial-training induced CREB activation, as well as impaired long term memory for the social transmission of food preferences secondary to the lack of late long term potentiation at the hippocampal area CA1 synapses (Peters et al. 2003; Mizuno et al. 2007). No difference was found in other types of hippocampus dependent long term memory, including contextual fear memory and passive avoidance, compared to wild-type mice suggesting that the formation of these long term memory types do not require the activation of CREB by CaMKKβ.
"I lost my keys again," my mother exclaimed at dinner a few nights ago, "I really am getting old." This use of old age as a justification for memory deficits is extremely common. Many people relate old age with loss of memory and other neurobiological functions. Why is it that aging seems to go hand in hand with losing and forgetting things? Is there a neurobiological explanation for this phenomenon?
Unless you have an eidetic memory, there have been points in your life where your memory has failed you. We all have had times where we are unable to recall certain memories. What if there was a supplement out there that could help with this? There are certain companies out there that would like to make you believe that there are magic pills out there that can do this. However, supplements are not effective with memory the way they advertise. Even if studies show that these supplements do not improve your memory they are still being sold and advertised as if they do. You have seen advertisements for these