Biopsych seminar 2020

In these papers, Ramirez et al. strive to understand how memory encoding via optogenetic manipulation of engram-bearing cells in the hippocampus, specifically the dentate gyrus, can affect an animal’s response to a stressful context.  The first paper, published in 2013, was crucial to the field as it introduced this very exciting technique; in this paper, Ramirez et al. use tet-tag to manipulate brain circuity and establish associations between two contexts. Throughout the paper, this is referred to as “false memories.” Using these artificial memories, the investigators are able to manipulate the animal’s fear response in a specific context. Specifically, after the animals are conditioned to a repeated fearful stimulus (a foot shock, in context B), activation of the involved DG cells in a different context (context A’) will also initiate a fear response (in absence of any foot shock). In this experiment, the false memory is used to create an unnatural fear association in a given...

Ramirez et al. (2013 & 2015) presents a very interesting and novel approach towards not only understanding mnemonic circuitry but also gaining temporally precise control of synthetic memory activation. Amongst both papers, the tet-tag system is used to recruit and reactivate engrams of neurons, a powerful tool when it comes to understanding how encoded memories of context or social interaction can modulate an animal’s ability to respond to stress.              The first paper, published in 2013, presents initial convincing data on the efficacy of this technique.  When the initial context (A) is encoded into the same engram as a shocking stimulus, although the mouse can be placed in an entirely different context, when the initial context is activated, along with it a fear response is activated. One very interesting dimension of the data shown is the competitive encoding and retrieval of contexts and fear. F...

This week an article by Ramirez et al. 2013, introduces the ability to create false memories in the hippocampus by optically stimulating cells that are associated with positive memory during negative events. This idea is then implemented two years later in the paper by Ramirez et al. 2015, where they activate cells associated with positive memory to suppress depression like behaviors in mice.  The 2013 paper began by identifying a small population of granule cells in the dentate gyrus of the hippocampus that coded for contextual memory. They utilized doxycycline (DOX) fed mice and upon withdrawal to DOX and introduction of these mice into a novel context A, the cells of the DG that encoded this environment were activated. These mice also contained the transgene TRE-ChR2-mCherry, that upon DOX withdrawal elicited fluorescent expression allowing for the labelling of the specific cells that encoded the context A. (Fig 1B,C) Then to determine whether a novel fear memory c...

At a first glance, the two papers appear to build upon each other, primarily since they are by the same researchers and published two years apart. With more insight, it becomes clear that one paper investigates the negative, fear emotions involved in memory whist the later aims to investigate behavioural effect on positive memories. These are two separate paths in the brain brain that may relate to depressive behaviour. Thus, the latter includes information and findings from their previous research for further support, strengthening the understanding of brain regions relation to behaviour. The paper published in 2013, overall aims to investigate the dentate gyrus and CA1 neurons as well as the amygdala in relation to channelrhodopsin-2 and the effect that these have on false memory creation. The research was conducted on multiple brain areas, which became beneficial as it created an understanding to that optical reactivation of cells was contributing to false memories in differ...

Ramirez’s research group explores the role of the dentate gyrus in both false memory formation and repression of depressive like behaviors in papers published two years apart. These papers complement each other as the second 2015 elaborates and grows from the previous 2013 paper. Ramirez et al’s 2013 paper explored the effects of stimulating the Dentate Gyrus (DG) to create a false memory. To do this, mice were first exposed to context A. While exploring this novel environment, the neurons activated were located and marked. Then, the mice were fear conditioned with foot shocks in context B while the same neurons that were activated in context A were reactivated. Ultimately, the mice were exposed to context A’ again as well as a control novel context C. The mice then responded with a fear response of freezing in context A, despite never having been fear conditioned within the context, but showed no response in context C. This same response was not seen when the CA1 region of the hi...

The Chaudhury et al paper explored the neural circuit mechanisms involved in the dopamine modulation of certain symptoms of depression. In this study, the researchers looked at social interaction and sucrose preference as part of their social-defeat paradigm, which has been shown in the past to be indicative of depressive-like behaviors. Although I initially did not completely see the connection between the social-defeat stress model of depression and the tonic vs phasic firing of dopamine neurons, it seemed that susceptibility and resilience to stress played a role in the functional/behavioral effects of dopamine firing. It was interesting to see how chronic mild stress with phasic firing of VTA dopamine neurons converted even resilient mice into susceptible mice.  The Tye et al paper similarly looked at the dopamine modulation of depressive-like behaviors, focusing on motivation with the forced swim tests and open field tests, followed by measurement of anhedonia by quantifyi...

In Tye’s 2012 paper, she utilized optogenetic stimulation of VTA dopamine neurons to study the role of said cell firing in depression. She found that inhibition of VTA DA neurons induces depression behaviors. Phasic activation of these neurons leads to symptom reversal in these mice with increased escape behaviors in tail suspension and sucrose preference. Further, she wanted to study cell firing in lasting depression-induced with a chronic mild stress paradigm. In this case, phasic activation of these cells also reversed symptoms. She wanted to see the necessity of dopamine and glutamate receptors. In the case of a glutamate agonist, struggling behaviors increased overall. Dopamine-blockade reduced struggling and is required for escape behaviors. Phasic activation of these VTA DA neurons requires functional DA receptors and the NAc neurons encode for this activation and escape behavior. Altogether, she found that VTA DA neuron firing underlies anticipating receipt o...

            This week we looked at two similar articles which focused on the neural circuits of the mid-brain, specifically the dopamine neurons in the ventral-tegmental area (VTA) as well as projections to the nucleus accumbens (NAc). The Chaudhury et al. paper investigates how different firing patterns of dopamine neurons (phasic or tonic) with the VTA and NAc regulate depression like behavior. After exposing the mice to 10-day social-defeat stress, Chaudhury found that susceptible (depressed) mice had increased phasic firing, while resilient mice (normal) mice had no changes in firing patterns. Using optogenetics to promote phasic firing, they immediately induce depression like behavior both susceptible and resilient mice, measured in increased social avoidance and decreased sucrose preference. Furthermore, they showed that inhibition of this pathway between the VTA and NAc would immediately induced a resilient phenotype. The ...

Much like the articles from our first class discussion, Tye et al. and Chaudhury et al. report on studies with similar focuses and end with different but complementary conclusions. Both papers introduce the concept that dopamine neurons in the brain’s reward circuit play a crucial role in the underpinnings of stress-induced depression-like phenotypes. Both studies also choose to investigate this claim through the use of optogenetics and the excitation or inhibition of neuronal pathways from the ventral tegmental area (VTA). Chaudhury et al. looks at these projections to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) while Tye et al. looks only to the NAc. A primary difference in the experiments are the stress paradigms utilized and the behavioral measures assessed afterward. Tye et al. employed the chronic mild stress (CMS) paradigm which has previously been shown to produce decreases in motivation as well as anhedonia. Similar results were found here with effects re...

Tye et al. This paper used optogenetic stimulation to induce depressive-like behavior and to stop depressive-like behavior in mice exposed to CMS-induced stress. They measured depressive-like behavior as social avoidance shown by decreased social interaction and anhedonia shown by decreased sucrose preference. They induced depressive-like behavior by expressing halorhodopsin in VTA dopamine neurons and optogenetically activating them (depressing the neurons). They also showed that deactivating them (removing illumination) immediately reverses the depressive-like behavior. Then they exposed mice to chronic mild stress and used optogenetic stimulation to activate channelrhodopsin expressed in the VTA dopamine neurons. Activation of channelrhodopsin opens these channels to increase dopamine transmission. Depressive-like behavior was present in mice without illumination and were reduced in mice with ChR2 that have been exposed to CMS. They also investigated the neuronal activity of the V...