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image courtesy of Taamannae Taabassum:

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3. While the authors of the paper looked at behavioral tests and used BrdU and AraC to address proliferation, an important part of the paper they wanted to address was the mechanism by which enriched environments rescue social memory. These pathways are still not clear but the paper did not address any potential genomic or molecular machinery by which this is done.

Some studies have shown that Arginine vasopressin plays an important role in learning and memory. When the posterior pituitary gland was removed, rats showed issues in impaired active avoidance shuttlebox performance, which was then recovered by Arginine vasopressin. (Ferguon et al. 2002)

Some studies suggest Dopaminergic and noradrenergic models for this. (Ferguon et al. 2002)

Since smell is highly important to rats, the olfactory bulb must be extremely important to social memory and recognition.

4. Stress plays a big factor in this study. The authors directly discussed the importance of reducing stress. It would have been better to see a less stressful test. i.e using the Zero maze instead of the evaluated plus maze test.

Studies showed that rats preferred the openness of the Zero maze compared to the plus maze. This leads us to believe that the plus maze may inhibit exploratory behavior and thus increase anxiety. (Braun et al. 2011)

Re-doing the test with the zero maze may impact the results and show more promising results.

Also, despite the fact that they studied anxiety, they did not look for any other signs of stress.

Stress impacts BDNF production, so the authors could have used this to look at stress levels

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Image Citation:  "The biochemistry of memory". Dart Neuroscience. 2015

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Image citation: Garcia et al. "Therapeutic effects of the transplantation of VEGF overexpressing bone marrow mesenchymal stem cells in the hippocampus of murine model of Alzheimer’s disease"  Front Aging Neurosci. 2014

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Image citation:  Shannon He. "Maze Basics: Elevated Maze". Maze Engineers. May 29, 2017

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● Adult male Swiss mice (8-12 weeks old; the exact sample size was not specified ) were divided into 4 groups:
image courtesy of Taamannae Taabassum:

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Critical Analysis: TLDR and how to address these issues in the future

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Critical Analysis: TLDR and how to address these issues in the future

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1. Rats rely heavily on their sense of smell. For this particular paper, the groups of mice that were supposed to be socially isolated were not fully isolated. The authors did not block the odour of the other rats.  This may have impacted the truly "isolated" nature of the experiment.

A suggested experiment would be to fully isolate the rats from all odors social memory.

A side experiment would be to lesion the olfactory bulb of rats and see the impact of it on social memory.

One would expect to see even more deleterious effects on social memory. The expectation would be that the olfactory bulb may behave like the hippocampus because, for their AraC experiment, they saw no difference in saline and inhibited groups

2. While social isolation had a detrimental and evident impact on neurogenesis, and the paper only focused on the long-term memory and the mechanism behind enriched environments and neurogenesis. Despite this, they stated that short-term social isolation did not decrease neurogenesis but it did have a detrimental impact. They did not provide any mechanism for this

The cAMP responsive element binding protein (CREB) is a protein that has a big impact on many biological functions. One such function is memory formation but only long-term memory, not short term.(Silva et al, 1998).

Therefore, one explanation for the lack of consolidation of long-term memory may be that this pathway is disrupted in the hippocampus

To test this, the authors could knock down this gene and see the impact on it on rats and social isolation

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What is neurogenesis and why is it important? 

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What is neurogenesis and why is it important? 

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Neurogenesis is the process of neuronal birth from stem cells. The adult has 2 locations where neurogenesis occurs: the subventricular zone and the hippocampus. This is important because it allows for the ability to learn, adapt and form new memories.

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The lab of Pierre-Marie Lledo researches the generation of new neurons in the adult brain. Even at a later age, new neurons are continously generated and effect the ability to learn. Research on adult neurogenesis, the generation of adult-born neurons in the human brain.

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To summarize all results, the researchers found that enriched environment is able to increase the rate of neurogenesis in the hippocampus and improve social memory formation. Neurogenesis is also a mechanisms necessary for enriched environment to work. Social isolation, although does not alter the rate, does inhibit long term social memory formation, a phenotype which can be blunted by EE, when administered at the same time. In the olfactory bulb, there seems to be no relation between neurogenesis rate and food finding abilities.

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Olfactory bulb: the controversial results 

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Olfactory bulb: the controversial results 

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Another area the researchers examined for neurogenesis was the olfactory bulb, which they divided into four layers. The results they gathered showed that only in the glomerular layer (site of primary odor encounter) enriched environment was able to increase neurogenesis rate regardless of housing conditions. To further examine the effects, thee performed a behavioural food finding task, which showed that mice housed in SI required more time to find hidden chocolate. After repeating the buried food task, but this time using the neurogenesis inhibitor AraC, the found no difference between the saline control and the AraC inhibited groups. These results suggest that there is no relation between housing conditions and neurogenesis rate in the olfactory bulb. However, the fact that the researchers did not take any steps to control the social odour mixing between socially isolated mice and other cages. Since odour recognition plays a very important role in life and survival of mice, the mixing of smells could have played a stimulatory effect, thereby the mice were not truly isolated. A step to be taken in the future is to ensure complete isolation of the SI and SI+EE groups and repeat the buried food finding tasks.

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NAD+ NeuroGenesis Therapy For Anxiety and Depersonalization Disorder

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Michael shares how NeuroGenesis therapy with NAD+ helped alleviate his anxiety and act as a catalyst for profound emotional connections. He expresses how his experience at NAD Treatment Center in San Diego gave him insight and a plan for managing the depersonalization disorder.

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Dietary modulation of brain plasticity: Implications for mental health

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To watch the full lecture visit: http://bit.ly/2k8aAVt About this lecture: Dr Sandrine Thuret discusses how diet can have implications on mental health and neurogenesis. Dr Thuret talks about the effects of diet on mood, in particular depression, and memory, including spatial memory capacity and pattern separation.

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Vijaya Sawant (http://oratechsolve.com/neurogenesis-formation-of-memories/₎

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Future Direction: Questions remaining in the field

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Future Direction: Questions remaining in the field

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-> Are there any differences between males and females in terms of EE recovery?
->Would short term EE and SI exposure have similar results on spatial memory?

->How does social isolation affect cells of the olfactory bulb under more controlled settings?

-> Explore the molecular mechanisms underlying short-term social memory inhibition by the SI
->Is there a more precise method to predict the effect on behavioral data of increasing neurogenesis in the olfactory than the food finding task?
-> Would EE conditions rescue social long term memory in mice housed in SI from birth?

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● Social recognition task - testing long-term social memory by determining the amount of time the adult mice spend getting to know a familiar juvenile mouse
● Elevated plus maze - comparing mice anxiety levels by determining the proportion of time mice spend in open arms (preference to enclosed habitat vs. exploring instinct)
● Buried Food-Finding Task - checking for the olfactory skills by determining the amount of time required for mice to find a familiar buried food hidden in a cage
● Immunofluorescence using BrdU - determining neurogenesis rate in brain areas
● Ara-C injection - blocking neurogenesis in injected area

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Thus, one future direction would be to look at the protein expression profile in the DG neurones during SI and EE. It has been previously shown that BDNF is a mediator of neurogenesis and its over expression can locally increase cell proliferation (Quesseveur G., 2015). It is also known that enriched environment increases BDNF transcripts in the cell (Jha S., 2001) , thus it would be expected to see a significant difference in BNDF transcript in mice house in enriched environment and controls.

Although SI showed no difference in neurogenesis rate from control, it was still able to impair social memory formation. It can be hypothesized, that although SI does not affect the rate of neurogenesis, it might affect some other factors implicated in memory formation. It would be interesting to compare protein expression profiles between groups.

To eliminate stress as a confounding variable, the anxiety levels of mice were tested by the evaluated plus maze test. A better test would be the zero test, which reduces the possible confusion of mice

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Although it was shown that enriched environments will help improve social memory, the authors of this paper wanted to outline the mechanisms by which enriched environments improve social memory. They hypothesized that this is done through the influence of enriched environments on neurogenesis. This would make sense as past papers have shown the positive impact of enriched environments on the brain. Enriched environments have shown to increase neurogenesis in the dentate gyrus.

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Why is social isolation vs enriched environments important?

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Why is social isolation vs enriched environments important?

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Social isolation is known to lower neurogenesis and stunts their rate of survival and differentiation in the subventricular zone and hippocampus. With this, we'd expect a phenotypic response of terrible memory and difficulty learning; both of which are bad. This is especially dangerous for rats since neurogenesis in the subventricular zone has neurons that migrate to the olfactory bulb, which is important for the sense of smell. For rats, the sense of smell is very important since they use it for food detection and friend vs. predatory identification.

It is thought that an enriched environment will help to recover social memory, increase neurogenesis in the dentate gyrus of the hippocampus, and improve spatial awareness and spatial memory.

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What is an enriched environment vs social isolation?

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What is an enriched environment vs social isolation?

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Specifically pertaining to rats, social isolation is the lack of stimulation from members of their own species. It has been shown that social memory will not be retained for more than 1 hour for a mouse that underwent social isolation. Social isolation is associated with depression and cardiovascular disease.

In terms of the neuroscience, social isolation has shown to reduce prefrontal cortex volume and impacts plasticity of the hippocampal synapses. On top of this, social isolation has shown an impact on neurotransmitters such as serotonin, dopamine and glutamate.

An enriched environment (EE) is an established residence that has elements which make it mentally and physically beneficial for the rats. Some of these elements include toys, ropes, different textures, and running wheels (Slater A., 2015). These enriched environments are helpful for the rats as they can reduce stress (Xu J., 2015), improve synaptic plasticity and cognitive deficiency (Bayat M., 2015.

Image citation: “Standard Cage vs Enriched Environment.” Scientiaportal, BSCS, 1 Nov. 2015

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AraC infusion experiment suggests that although neurogenesis is not implicated in effects seen from SI housing (as suggested by previous experiment), it is, however, a mechanism necessary for the recovery made by enriched environment.

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Enriched environment increases the rate of neurogenesis independent of the housing conditions. Short term social isolation at the same time did not alter neurogenesis rate, however still had deleterious effects of memory formation, suggesting it works through a separate mechanisms.

Other studies have shown that social isolation does impair neurogenesis when administered at early stages of development (McCormic CM., 2012), this paper examines only the effects of short-term isolation administered for one week in adults.

However, the authors only look at behavioural data and did not perform any experiments to examine effect of EE and SI on molecular expression.

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Even short term social isolation of 7 days is able to significantly inhibit social memory formation in adults. A deficit, which can be recovered by an enriched environment.

This is the first paper to examine the recovery made by EE in mice housed in social isolation at the same time. This demonstrates the difference an enriched environment can have on an adult mouse brain even in conditions of social isolation. In the future, it would be interesting to examine whether the same interplay between SI and EE can be observed in spatial memory.

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Conclusions, Analysis, and Future Directions 

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Conclusions, Analysis, and Future Directions 

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Figure 6. Time spent investigating by SI mice in EE. With neurogenesis blocked, EE is not able to recover the deficit, as seen in the saline control, and mice do not retain memory of previous encounter.

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Figure 5. Density of BrdU/NeuN + cells in the DG upon AraC infusion

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Figure 3. Double staining with BrdU and NeuN of the DG in the hippocampus.
Figure 4. Density of BrdU/NeuN+ cells between groups. EE increases rate regardless of housing.

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Figure 1. Evaluation of retention of short-term memories (30 mins).

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Figure 2. Times spent on social investigation evaluating long-term memory (24 hours). Social isolation blocks long term memory retention. An enriched environment is able to recover the deficit.

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Performing social recognition task showed that the enriched environment was no longer able to blunt the deleterious effects of social isolation. This demonstrates that neurogenesis plays an essential role in long-term memory consolidation and is utilized in the mechanisms through which enriched environment affects social memory.

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To examine the necessity of neurogenesis for the ameliorating effects of enriched environment a neurogenesis inhibitor AraC was administered for 7 days to the socially isolated group of mice in an enriched environment. The controls were administered a saline infusion.

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By double staining neurons with BrdU (marker for proliferation) and NeuN (neuronal marker) the researchers were able to quantify neurogenesis.
What they discovered was that SI did not alter neurogenesis, whereas EE was able to increase the rate of neurogenesis in both the controls (GH+EE) and the socially isolated mice (SI+EE). This partially proved their hypothesis. To the further examine whether neurogenesis was a mechanism necessary for the effects of an enriched environment to take place, AraC infusion was performed.

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Schinder A.F., Gage F.H. A hypothesis about the role of adult neurogeneisis in hippocampal function. Physiology, 19:5 253-261. 2004.

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1. Bayat, M., Sharifi, M. D., Haghani, M., & Shabani, M. (2015). Enriched environment improves synaptic plasticity and cognitive deficiency in chronic cerebral hypoperfused rats. Brain Research Bulletin, 119, 34–40. https://doi.org/10.1016/j.brainresbull.2015.10.001

2. Fabricius, K., Helboe, L., Steiniger-Brach, B., Fink-Jensen, A., & Pakkenberg, B. (2010). Stereological brain volume changes in post-weaned socially isolated rats. Brain Research, 1345, 233-239. doi:10.1016/j.brainres.2010.05.040
3.Braun, A. A., Skelton, M. R., Vorhees, C. V., & Williams, M. T. (2011). Comparison of the elevated plus and elevated zero mazes in treated and untreated male Sprague-Dawley rats: Effects of anxiolytic and anxiogenic agents. Pharmacology Biochemistry and Behavior, 97(3), 406–415. https://doi.org/10.1016/j.pbb.2010.09.013

4. Ferguson, J. N., Young, L. J., & Insel, T. R. (2002). The Neuroendocrine Basis of Social Recognition. Frontiers in Neuroendocrinology, 23(2), 200–224. https://doi.org/10.1006/frne.2002.0229

5. Garcia, K. O., Ornellas, F. L. M., Matsumoto Martin, P. K., Patti, C. L., Mello, L. E., Frussa-Filho, R., … Longo, B. M. (2014). Therapeutic effects of the transplantation of VEGF overexpressing bone marrow mesenchymal stem cells in the hippocampus of murine model of alzheimer’s disease. Frontiers in Aging Neuroscience, 6(MAR), 1–15. https://doi.org/10.3389/fnagi.2014.00030

6. Jha, S., Dong, B., & Sakata, K. (2011). Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV. Translational Psychiatry, 1(9), e40-11. https://doi.org/10.1038/tp.2011.33

7. Khodaie, B., Lotfinia, A. A., Ahmadi, M., Lotfinia, M., Jafarian, M., Karimzadeh, F., … Gorji, A. (2015). Structural and functional effects of social isolation on the hippocampus of rats with traumatic brain injury. Behavioural Brain Research, 278, 55–65. https://doi.org/10.1016/j.bbr.2014.09.034

McCormick, C. M., Thomas, C. M., Sheridan, C. S., Nixon, F., Flynn, J. A., & Mathews, I. Z. (2012). Social instability stress in adolescent male rats alters hippocampal neurogenesis and produces deficits in spatial location memory in adulthood. Hippocampus, 22(6), 1300–1312. https://doi.org/10.1002/hipo.20966

8. Quesseveur, G., David, D. J., Gaillard, M. C., Pla, P., Wu, M. V., Nguyen, H. T., … Guiard, B. P. (2013). BDNF overexpression in mouse hippocampal astrocytes promotes local neurogenesis and elicits anxiolytic-like activities. Translational Psychiatry, 3(March). https://doi.org/10.1038/tp.2013.30

9. Remondes, M., & Schuman, E. M. (2004). Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory. Nature, 431(7009), 699–703. https://doi.org/10.1038/nature02965

10. Schinder, A. F., & Gage, F. H. (2004). A hypothesis about the role of adult neurogenesis in hippocampal function. Physiology, 19, 253–261. https://doi.org/10.1152/physiol.00012.2004

11. Silva, A. J., Kogan, J. H., Frankland, P. W., & Kida, S. (1998). Creb and Memory. Annual Review of Neuroscience, 21(1), 127–148. https://doi.org/10.1146/annurev.neuro.21.1.127

12. Slater, A. M., & Cao, L. (2015). A Protocol for Housing Mice in an Enriched Environment. Journal of Visualized Experiments : JoVE, (100), e52874. https://doi.org/10.3791/52874

12. Takeuchi, T., Duszkiewicz, A. J., & Morris, R. G. M. (2013). The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philosophical Transactions of the Royal Society B: Biological Sciences, 369(1633), 20130288–20130288. https://doi.org/10.1098/rstb.2013.0288

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Next, to test the hypothesis regarding mechanisms by which memory formation is affected, the researchers looked at the hippocampus. The hippocampus is an area responsible for memory formation, specifically examining the dentate gyrus (DG) and area with neurogenesis restricted to it.

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Why is social memory and social interaction so important?

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Why is social memory and social interaction so important?

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Social memory is the mechanism by which recognition occurs. Recognition of friend or foe allows individuals to behave appropriately. These interactions also help to improve everyday knowledge about the world, thus improving one's chance of survival. For humans, the site of other human faces will activate the ventral temporal lobe. Interestingly, social memory can be heavily impacted by environmental factors.

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Social Interaction & Performance: Crash Course Sociology #15

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Researchers discovered that adult mice placed in social isolation, even for a short period of 7 days, had impacted memory formation, and were unable to form long-term memories. An effect correlated with a decrease in BrdU+/NeuN+ cells in the hippocampus. They also found, that enriched environment is able to reduce the impact of social isolation, recovering memory forming abilities. These results demonstrate the importance of an enriched environment and mental stimulation and their promotion of memory enhancement even in adult specimens.

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To measure the capabilities of mice to form long term memories a social recognition task was performed. And adult mouse was introduced into a cage containing a pup and the time spent interacting was examined. During the training session (TR) the pup was a novel object, thus the adult spent more time investigating. If they retain the memory of the interaction, then during the second test session (TT) measured 24 hours post TR, the pup would no longer be novel and less time will be spent on investigation.

No difference was found between socially isolated and group housed mice and their abilities to retain short term memories.

Examining long term memory, it becomes apparent that social isolation affects memory retention, as no significant difference was found between TR and TT for the SI group.

The second discovery demonstrates the ability of an enriched environment to blunt the deleterious effects of social isolation, as it is able to recover the wild type phenotype to some extent in SI+EE group.

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Group-Housed                 Socially Isolated             Group-Housed            Socially Isolated in
(GH)                                      (SI)                              (GH+EE) .        Enriched Environment (SI+EE)