Developing Research

This is an introduction that I will be working on throughout the summer.  Currently, it is what I submitted for the U. Discover grant with the addition of a working outline for my final thesis/publication:

Grant Proposal:

Early life stress and neglect are associated with the development of psychiatric disorders (e.g. anxiety and depression) later in life (National Clearinghouse on Child Abuse and Neglect Report, 2005; Espejo et al., 2007).  However, the neural mechanisms linking early life stress to depression and anxiety later in life are not well understood.  In rats, social isolation at an early age is used as a model for early life stress, and this stress also produces anxiety behaviors later in life (Lukkes et al., 2009b).  Stress is thought to result in the release of corticotropin-releasing factor (CRF) into the dorsal raphe nucleus (dRN) where it acts on serotonin (5-HT) cells in the dRN.  The release of CRF and the release of the 5-HT from the dRN are both associated with the stress response (Bale, 2005; Forster et al., 2006).  Rats reared in isolation during early life have an increased number of CRF2 receptors in the lateral wings of the dRN in adulthood (Lukkes et al., 2009a).  Furthermore, isolation in early life caused the prolonged release of 5-HT in the adult brain after the infusion of CRF into the dRN.  It is thought that this is a result of the increased number of CRF2 receptors in the dRN (Lukkes et al., 2009a).   A recent study in the Forster Laboratory showed that infusion of a non-selective CRF receptor antagonist, binding to both CRF1 and CRF2 receptors, into the dRN alleviates the increased anxiety behaviors associated with the isolation-reared rats (Lukkes et al., submitted).  Based on previous research, we hypothesize that early life social isolation increases the number of CRF2 receptors in the dRN to increase anxiety behavior.  The goal of this study is to determine if blocking the CRF2 receptors with a CRF2 receptor antagonist will reduce anxiety behaviors in adult rats exposed to early life social isolation.

Sources:

Bale, T.L. (2005). Sensitivity to stress: Dysregulation of CRF pathways and disease development. Hormones and Behavior 48: 1-10.

Espejo, E.P., Hammen, C.L., Connolly, N.P., Brennan, P.A., Najman, J.M, Bor, W. (2006). Stress sensitization and adolescent depressive severity as a function of childhood adversity: A link to anxiety disorders. Journal of Abnormal Child Psychology 35: 287-299.

Forster, G.L., Feng, N., Watt, M.J., Korzan, W.J., Summers, C.H., and Renner, K.J. (2006). Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior. Neuroscience 141: 1047-1055.

Lukkes, J.L., Summers, C.H., Scholl, J.L., Renner, K.J., Forster, G.L. (2009a). Early life social isolation alters corticotropin-releasing factor responses in adult rats.  Neuroscience 158: 845-855.

Lukkes, J.L., Mokin, M.V., Scholl, J.L., Renner, K.J., Forster, G.L. (2009b).  Adult rats exposed to early-life social isolation exhibit anxiety and conditioned fear behavior, and altered hormonal stress responses.  Hormones and Behavior 55: 248-256.

Lukkes, J.L., Vuong, S.M., Oliver, K., Scholl, J.S., Oliver, H., Forster, G.L.  Corticotropin-releasing factor receptor antagonism reduces social anxiety following early-life social isolation.  Journal of Neuroscience, submitted.

National Clearinghouse on Child Abuse and Neglect. (2005). Long-term consequences of child abuse and neglect. U.S. Department of Health and Human Services.

OUTLINE:

I. Importance and Significance

II. Dorsal Raphe Nucleus

-What it is, what it does/controls, where it is.

III. Early-life stress and isolation

-Explain model

-Goal: establish understanding of connection between early-life stress and                 social isolation.

IV. “Pathway” Section

-early life stress=increase in CRF2 Receptors in dRN.

-Stress=release of CRF from hypothalamus to dRN.

-CRF causes release of 5-HT into NAc (among other regions) from 5-HT cell             bodies in dRN causing anxiety

V. EPM

-about, how it observes stress, normal behavior

VI. CRF2 receptor antagonist

-About, how it works, how it stops anxiety behavior via above pathway.

VII.  Hypothesis and goal of research.

Alleviating anxiety behavior caused by early-life stress through corticotropin-releasing factor II antagonism

Abstract

Early life stress is associated with the development of psychiatric disorders (e.g. anxiety and depression) later in life. Stress is thought to result in the release of corticotropin-releasing factor (CRF) into the dorsal raphe nucleus (dRN) of the brain.  In the dRN, CRF acts on serotonin (5-HT) cells, and the release of CRF and 5-HT from the dRN are both associated with the stress response.  Rats reared in isolation show increased anxiety behavior and have an increased number of CRF2 receptors in the lateral wings of the dRN in adulthood.  Based on previous research, we hypothesize that early life social isolation increases the number of CRF2 receptors in the dRN to increase anxiety behavior.  The aim of this study is to determine if blocking the CRF2 receptors with a CRF2 receptor antagonist will reduce anxiety behaviors in adult rats exposed to early life social isolation.  The study will determine if an infusion of ASV-30 (CRF2 receptor antagonist, 2mg/0.5mL) will result in normal anxiety behavior (similar to that of the group-reared rats) in the socially isolated rats compared to those given a vehicle solution.  Overall, the results from this research could lead to a more focused pharmacological treatment of anxiety.

Introduction

Early-life stress and neglect are associated with the development of psychiatric disorders (eg: anxiety and depression) later in life (National Clearinghouse on Childhood Abuse and Neglect Report, 2005; Espejo et al., 2007).  It is important to understand the mechanism behind this association in order to develop more targeted treatments.  Rats reared in social isolation (alone in a cage) is a model for early-life stress, and it is shown that these rats display increased adult anxiety behavior (Hall, 1998).  This anxiety behavior is most evident in the open field and social interaction when the rats are reared in social isolation over the period of adolescence (van den Berg, 1999; Lukkes, 2009b).  It is evident that early-life stress caused by social isolation is associated with the development of psychiatric disorders later in life, but the neural mechanisms by which this occurs are not well understood.  A more thorough understanding of the mechanism could lead to more effective ways to prevent or treat these disorders.

The rearing of rats in social isolation is a model for studying early-life stress.  Rats reared in social isolation have anxiolytic effects on behavior that remain into adulthood (Heidbreder et al., 2000; Varlinskaya et al., 1999).  It has been shown that social isolation beginning at the time of weaning is critical in producing anxiety behavior later in life (Weiss et al., 2004; Arakawa, 2005).  Varlinskaya et al. (1999) found that the best time to isolate rats in order to study early-life stress’s effects on anxiety behavior is between weaning and sexual maturation.  These anxiety behaviors (measured in the open-field and social interaction), caused by early-life social isolation, remain even if the rat has been re-housed into a group cage after the isolation period following weaning (Varlinskaya et al., 1999; Pascual et al., 2006).  The current experiment has been developed to incorporate these principles: social isolation beginning at the time of weaning and re-housing the animals to prevent current stress at the time of testing.  In understanding the data showing that isolation from the time of weaning still expresses anxiety behavior in adulthood, re-housing the animals prior to testing should have no effect on the anxiety behavior created by early-life social isolation.  Social isolation of rats immediately after weaning provides a model for studying the effects of early-life stress, regardless of re-housing later in life.

Van den Berg et al. (1999) explain several methods of measuring anxiety behavior in rats, specifically in response to social isolation.  These include the social interaction test, open-field test, elevated plus maze, shock-prod test, resident-intruder/social defeat test, and the sexual behavior test.  In the social interaction test, the animas behavior is scored based on video footage recording interactions with another animal.  The open-field test involves a novel object (a glass jar filled with lead in the case of van den Berg et al.)in an arena and video of the animals behavior is scored, looking for signs of anxiety.  The elevated plus maze, which the current experiment utilizes, is described in detail later in the paper.  The shock-prod test involves recording anxiety behavior after a shock is administered to the animal.  The resident-intruder or social defeat test observes changes in blood chemistry in response to social bullying.  Finally, changes in sexual behaviors can be measured when introduced to a sexually receptive female.  These tests can all measure anxiety behavior, including that caused by social isolation, and the current study utilizes the elevated plus maze.

In order to begin to understand the correlation between early-life stress and anxiety symptoms in early-adulthood, one must consider what is known of the physiological processes involved.  Corticotropin-releasing factor (CRF) is directly involved in responses to stressors (Bale, 2005).  CRF is commonly involved in activating the endocrine system, but also serves as a neurotransmitter in the central nervous system (CNS).  CRF acts on two major types of receptors in the CNS: CRF1 and CRF2 receptors (Gregoriadis et al., 2006).  CRF1 receptors are found in neocortical, cerebellar, and sensory structures, while CRF2 receptors are more localized to subcortical areas and hypothalamic nuclei (Chalmers et al., 1995).

In humans, it has been observed that changes in cerebrospinal fluid (CSF) CRF concentrations correlate with increased symptoms of anxiety and depression (Arborelius et al., 1999).  CRF is known to be involved in anxiety behavior in animal models (Bale, 2005).  For example, ventricular infusion of a CRF2 receptor antagonist (ASV-30), or a combination CRF1/CRF2 receptor antagonist (astressin), both reduced anxiety behavior in the open field, plus maze, and marble burying tests of anxiety in mice (Pellymounter et al., 2002).

CRF stimulation seems to control the release of serotonin (5-HT) from the dorsal raphé nucleus (dRN) in the brainstem (Price & Lucki, 2001).  Serotonin has been shown to regulate anxiety behavior, especially that released from the dRN in response to CRF stimulation (Lowry et al., 2005).  Infusion of CRF into the dRN resulted in increased 5-HT levels in forebrain regions related to stress and anxiety, such as the central nucleus of the amygdala (CeA), the medial prefrontal cortex (mPFC) (Forster et al., 2006), and the nucleus accumbens (Lukkes et al., 2008).  It has been found that CRF2 receptors in the dRN promote the release of 5-HT in the forebrain, and there seems to be a connection between the concentration of CRF present and whether the response to CRF is inhibitory or excitatory (Amat et al., 2004, Lukkes et al., 2008).  This is because CRF has a higher affinity for CRF1 vs. CRF2 receptors (Janh et al., 2004), thus at lower concentrations CRF activates CRF1 receptors which appears to inhibit 5-HT neurons and reduces 5-HT release, whereas at higher concentrations CRF binds to CRF2 receptors as well, which activate 5-HT neurons and increases 5-HT release (Bale, 2005; Pernar et al., 2004; Lukkes et al., 2008; Forster et al., 2008).

Rats reared in isolation during early life have an increased number of CRF2 receptors in the lateral wings of the dRN in adulthood (Lukkes et al., 2009a).  A recent study has shown that the infusion of a non-selective CRF receptor antagonist, binding to both CRF1 and CRF2 receptors, alleviated the anxiety created by the rearing of the rats in early-life social isolation (Lukkes et al., 2009c).  While early-life stress is known to cause anxiety behaviors when measured in early adulthood, it is not known if the anxiety is mediated by CRF1 or CRF2 receptors.  This study aims to determine which receptor is involved in this process.

In order to measure anxiety behavior in rats, the elevated plus maze (EPM) has been developed, which shows relative reliability in measuring rodent anxiety behavior.  This maze is raised off the ground and has two arms arranged ninety degrees from each other.  One arm, the closed arm, has walls around the platform, while the other arm, the open arm, does not have any enclosure.  More time spent in the open arm is indicative of decreased anxiety (Dawson & Tricklebank, 1995).  The open-arm creates a sense of fear in the animal because of the necessity to balance on a narrow platform.  Conversely, the closed-arm’s walls provide a sense of security with no fear of falling off of the maze.  This test is given validity due to its use of natural stimuli that can cause anxiety in humans (Dawson & Tricklebank, 1995).

It is important to monitor that the total distance moved in the maze of each rat in order to ensure the distance is similar, because if the treatment changes mobility, the EPM is not an accurate method of observing anxiety behavior (Lapiz-Bluhm et al., 2008).  If there is an inconsistency in total distance moved between two or more groups, the group with a lesser distance has a decreased opportunity to spend time in the open arms.  Having consistent mobility ensures that the test provides equal opportunity to enter and spend time in the open arms, ensuring consistent testing.  Furthermore, monitoring mobility ensures that a treatment does not result in altered motor functioning.  This could be due to experimental manipulations (ie. drug or rearing) either exciting or inhibiting brain regions involved in mobility.  It is essential to have consistent mobility between groups on the EPM to ensure valid results.

The EPM has advantages and disadvantages as an apparatus to measure anxiety-like behaviors of rodents.  Advantages include ease of use, inexpensiveness, and the rats do not have to be trained, deprived of any nourishment, or artificially stimulated.  Therefore, the maze measures unconditioned anxiety behavior (Dawson and Tricklebank, 1995).  Disadvantages include necessity of similar motor activity between treatment groups, inability to reuse animals after testing, and the possibility to habituation to the maze when testing effects of chronic drug abuse (testing anxiety behaviors due to drug administration more than once on the EPM) (Dawson & Tricklebank, 1995).  When looking at solely the effects of a drug on anxiety, the EPM appears to providing conflicting results (Pinheiro et al., 2007).  In a study conducted by van den Berg et al. (1999), rats were socially isolated from Post-natal day (P) 28 to P-35, individually housed at the time of testing, and there were dim light conditions in the center of the maze at the time of testing.  This study found no statistical difference in anxiety behavior between isolates and group-housed animals.  This may be explained by the isolates being housed alone at the time of testing, the dim light in the maze at time of testing, and the time of weaning (van den Berg et al., 1999).  In the present experiment, accommodations have been made to decrease the effects of these outside variables.  All animals are re-housed into groups of three 14 days before surgery and remain in this arrangement through testing.  Very little light is present in the room, and it is filtered through a red-light filter.  Finally, the period of isolation extends from P-21 to P-42, increasing the length to include all of adolescence.  The EPM has become a tool to measure anxiety in rodents, and understanding its limitations will allow for accurate data to be collected efficiently.

To ensure the EPM was an accurate tool to measure the anxiety behavior caused by early-life isolation from P-21 to P-42 a pilot study was conducted in the Forster laboratory.  This study showed increased anxiety behavior on the EPM in early-life socially isolated rats, compared with group-housed rats.   In the pilot study, there was no difference in locomotion apparent between the two groups.  This study has taken into consideration the advantages and disadvantages of the EPM, and will monitor the total distance moved to ensure consistent testing, and each animal is tested only one time to ensure the novel environment of the EPM.  Based on pilot study results, the EPM serves as an accurate means of measuring anxiety behavior under the specific conditions of this experiment.

The current study is interested in further investigating the correlation between early-life stress and adult anxiety behavior in the context of CRF binding to CRF2 receptors near 5-HT cell bodies in the dRN.  Based on previous research, we hypothesize that early life social isolation increases the number of CRF2 receptors in the dRN to increase anxiety behavior.  The goal of this study is to determine if blocking the CRF2 receptors with a CRF2 receptor antagonist will reduce anxiety behaviors in adult rats exposed to early-life social isolation.  This would be significant in determining the precise mechanism involved in associating early-life stress to adult anxiety behaviors.

References

Amat, J., Tamblyn, J.P., Paul, E.D., Bland, S.T., Amat, P., Foster, A.C., Watkins, L.R., Maier, S.F. (2004). Microinjection of urocortin 2 into the dorsal raphé nucleus activates serotonergic neurons and increases extracellular serotonin in the basolateral amygdala. Neuroscience 129: 509-519.

Arakawa, H. (2005). Interaction between isolation rearing and social development on exploratory behavior in male rats.  Behavioural Processes 70: 223-234.

Arborelius, L., Owens, M.J., Plotsky, P.M., Nemeroff, C.B. (1999). The role of corticotropin-releasing factor in depression and anxiety disorders. Journal of Endocrinology 160: 1-12.

Bale, T.L., (2005). Sensitivity to stress: Dysregulation of CRF pathways and disease development. Hormones and Behavior 48: 1-10.

Chalmers, D.T., Lovenberg, T.W., De Souza, E.B. (1995). Localization of novel corticotropin-releasing factor receptor (CRF2) mRNA expression to specific subcortical nuclei in rat brain: comparison with CRF1 receptor mRNA expression. Journal of Neuroscience 15 (10): 6340-6350.

Dawson, G.R., Tricklebank, M.D., (1995). Use of the elevated plus maze in search for novel anxiolytic agents.  Trends in Pharmacological Sciences 16(2): 33-36.

Espejo, E.P., Hammen, C.L., Connolly, N.P., Brennan, P.A., Najman, J.M, Bor, W. (2006). Stress sensitization and adolescent depressive severity as a function of childhood adversity: A link to anxiety disorders. Journal of Abnormal Child Psychology 35: 287-299.

Forster, G.L., Pringle, R.B., Mouw, N.J., Vuong, S.M., Watt, M.J., Burke, A.R., Lowry, C.A., Summers, C.H., Renner, K.J. (2008). Corticotropin-releasing factor in the dorsal raphé nucleus increases medial prefrontal cortical serotonin via type 2 receptors and median raphé nucleus activity. European Journal of Neuroscience 28(2): 299-310.

Forster, G.L., Feng, N., Watt, M.J., Korzan, W.J., Summers, C.H., and Renner, K.J. (2006). Corticotropin-releasing factor in the dorsal raphe elicits temporally distinct serotonergic responses in the limbic system in relation to fear behavior. Neuroscience 141: 1047-1055.

Grigoriadis, D.E., Lovenberg, T.W., Chalmers, D.T., Liaw, C., Souza, E.B. (2006). Characterization of corticotropin-releasing factor receptor subtypes. Annals of the New York Academy of Sciences 780: 60-80.

Heidbreder, C.A., Weiss, I.C., Domeney, A.M., Pryce, C., Homberg, J., Hedou, G., Feldon, J., Moran, M.C., Nelson, P. (2000). Behavioral, eurochemical and endocrinological characterization of the early social isolation syndrome.  Neuroscience 100(4): 749-768.

Jahn, O., Tezval, H., van Werven, L., Eckart, K., Spiess, J. (2004). Three-amino acid motifs of urocortin II and III determine their CRF receptor subtype selectivity.  Neuropharmacology 47: 233-242.

Lapiz-Bluhm M.D.S., Bondi, C.O., Joyen, J., Rodriguez, G.A., Bedard-Arana, T., Morilak, D.A. (2008). Behavioural assays to model cognitive and affective dimensions of depression and anxiety in rats. Journal of Neuroendocrinology 20: 1115-1137.

Lowry, C.A., Johnson, P.L., Hay-Schmidt, A., Mikkelsen, J., Shekhar, A. (2005). Modulation of anxiety circuits by serotonergic systems. Stress 8(4): 233-246.

Lukkes, J.L., Forster, G.L., Renner, K.J., Summers, C.H. (2008). Corticotropin-releasing factor 1 and 2 receptors in the dorsal raphé differentially affect serotonin release in the nucleus accumbens. European Journal of Pharmacology 578: 185-193.

Lukkes, J.L., Summers, C.H., Scholl, J.L., Renner, K.J., Forster, G.L. (2009a). Early life social isolation alters corticotropin-releasing factor responses in adult rats.  Neuroscience 158: 845-855.

Lukkes, J.L., Mokin, M.V., Scholl, J.L., Forster, G.L. (2009b). Adult rats exposed to early-life social isolation exhibit increased anxiety and conditioned fear behavior, and altered hormonal stress responses. Hormones and Behavior 55: 248-256.

Lukkes, J.L., Vuong, S.M., Scholl, J.S., Oliver, H., and Forster, G.L.  (2009c). Corticotropin-releasing factor receptor antagonism within the dorsal raphé reduces social anxiety following early-life social isolation.  Journal of Neuroscience, in press.

National Clearinghouse on Child Abuse and Neglect. (2005). Long-term consequences of child abuse and neglect. U.S. Department of Health and Human Services.

Pascual, R., Zamora-León, S.P., Valero-Cabré, A. (2006). Effects of postweaning social isolation and re-socialization on the expression of vasoactive intestinal peptide (VIP) and dendritic development in the medial prefrontal cortex of the rat.  Acta Neurobiolociae Experimentalis 66:7-14.

Pelleymounter, M.A., Joppa, M., Ling, N., Foster, A.C. (2002). Pharmacological evidence supporting a role for central corticotropin releasing factor2 receptors in behavioral, but not endocrine, response to environmental stress. Journal of Pharmacology and Experimental Therapeutics 302: 145-152.

Pernar, L., Curtis, A.L., Vale, W.W., Rivier, J.E., Valentino, R.J. (2004). Selective activation of corticotropin-releasing factor-2 receptors of neurochemically identified neurons in the rat dorsal raphé nucleus reveals dual actions. Journal of Neuroscience 24(6): 1305-1311.

Pinheiro, S.H., Zangrossi-Jr., H., Del-Ben, C.M., Graeff, F.G. (2007).  Elevated mazes as animal models of anxiety: effects of serotonergic agents.  Anais da Academia Brasileira de Ciencias 79(1): 71-85.

Price, M.L., Lucki, I. (2001). Regulation of serotonin release in the lateral septum and striatum by corticotropin-releasing factor. Journal of Neuroscience 21(8): 2833-2841.

van den Berg, C.L., Hol, T., Van Ree, J.M., Spruijt, B.M., Everts, H., Koolhaas, J.M. (1999). Play is indispensable for an adequate development of coping with social challenges in the rat.  Developmental Psychobiology 34(2): 129-138.

Varlinskaya, E.I., Spear, L.P., Spear, N.E. (1999). Social behavior and social motivation in adolescent rats: role of housing conditions and partner’s activity.  Physiology & Behavior 67(4): 475-482.

Weiss, I.C., Pryce, C.R., Jongen-Rêlo, A.L., Nanz-Bahr, N.I., Feldon, J. (2004). Effect of social isolation on stress-related behavioural and neuroendocrine state in the rat.  Behavioural Brain Research 152: 279-295.


14 Responses to “Developing Research”

  1. Hello, Adam. Very intersting, indeed.

    I have two questions. The first of which aims to understand contemporary research on this subject. The last aims to understand the known effects of the binding process.

    My understanding is that prior research outlines an association between isolation and CRF2 receptors which, ultimately, suggests a higher likelihood, if not actual increase, for anziety behaviors. I am curious, however, if research has evaluated whether or not isolated rats stablize their anxiety behaviors over time and, if so, how long. It is clear that an association exists between isolation, time, and anxiety behaviors. However, logically speaking, it seems to me that the converse should be true that socialization (re-emerging from isolation to a “normal” social setting) reverses, if not stablizes, anxiety over time. In other words, the presence of the receptors in dRN should diminish over time. If the presence does not diminish, does the receptor’s use diminish over time? Alternatively, if the receptors that increase anxious behaviors exist, does that mean they necessarily will be evident during the course of the rats life? Ultimately, I am curious if the presence of these receptors and effect of them remains constant or, if they too, are diminished in effectiveness over time (the receptors exist yet the behavior, is diminished by the nature of the environment with respect to time).

    The second area of curosity I have centers on whether or not the effects of the binding itself are known. In other words, what is the long-term effect of this binding? Are there other consequences that contribute to structural change in the dRN, positive or detrimental? I know that these may be outside the scope of your research but, ultimately, as I see this relational to humans, I am sure that it is worthy of consideration.

    What are your thoughts on these matters?

    • Karl–Excellent questions. I have talked to Gina regarding the first question, and we do not know if the number of receptors decreases throughout adulthood after early life stress. However, a similar study using amphetamine could lend some insight. Amphetamine use causes a similar type of stress and increase of CRF2 receptors in the dRN. Six weeks after a rat’s last injection with amphetamine, the number of CRF2 receptors is even higher than the few weeks after the last amphetamine injection. It would seem that the number of CRF2 receptors would remain increased from this data, but data regarding early life isolation’s role has not been acquired.

      For the second question, the best way I could explain it is that early life stress causes an increased number of CRF2 receptors in the lateral wings of the dRN. These receptors are structures on serotonin cell bodies that project to different brain regions. When these receptors come into contact with CRF from the amygdala, they cause serotonin release. More receptors lead to greater serotonin release in some areas of the brain. We are attempting to “block” some of these receptors with a drug to alleviate the anxiety caused by the increased number of CRF receptors (caused by the early life isolation).

      Hope this answers your questions. If not, let me know and I can discuss this with you further.

  2. This sounds very interesting. You said this s research “could lead to a more focused pharmacological treatment of anxiety” so does that mean that your group is going to create an entirely new drug or just modify the drugs that are currently used? Also, how did you measure anxiety in your experiments? By if they explored or not? What about Depression? This project sounds very interesting and I look forward to see if you make any interesting discoveries.

    • Thanks. We are currently looking at a new drug to treat anxiety through a different pathway. It is in its really early stages, but so far, the results are looking promising. I will discuss the way we measure the anxiety in my discussion of the project in class. Thanks again for the the good questions.

  3. I may be slightly confused, but I was wondering what “early life stress” is? Does that include birth, or does it include older children? Your research sounds really impressive, though! That’s incredible that you’re working on such a large project that could make a difference in the lives of so many people. I hope it works out well for you.

    • Good question! The early-life stress we work with is stress in/through adolescence. It is simulated by isolation in adolescence. It has been shown to result in anxiety behaviors in early adulthood. I hope to explain this more thoroughly in my presentation in July. Thanks for the comments!

  4. At what point is the onset of this anxiety/stress evident? How long does it take for it to occur? Do these rats begin in isolation?

  5. You write a few times that this is going to be for your thesis/publication. Does this mean you are planning on publishing this in a scholarly journal? If so, I’m very impressed with that as well as the ground-breaking research you are conducting. Right now, I am curious if you will be posting any pictures of your surgeries on the blog to give a better idea of what you are working with. On that note, I am also wondering exactly what goes on during those surgeries.

    Best of Luck,

    B. F. Pons

    • Thanks! I will not be able to post photos, but I will be able to discuss the project in detail during my presentation to the class in July.

  6. Very impressive, Adam! I’m happy that your research is going so well! Nothing is more frustrating than to have set ups crash and burn. That being said, I’m going to ask the not-so-scientific question of how do anxiety and depression manifest behaviorally in a rat? Are you just measuring CRF? Or do you look for certain behaviors as well?

  7. Your paper is looking very good so far. I was wondering if you could explain to me in simpler terms how that it was determined that the EPM is a good measure of anxiety. I am just a little confused on that. Good luck with the rest of your research.

    • Josh…good question. I have updated information in my draft essay regarding how the EPM measures anxiety, and I will be discussing it in relative detail tomorrow in my presentation. If you still have questions regarding the EPM, please feel free to ask me about it after my presentation. Thanks–Adam

  8. Adam

    Really like the content of your blogsite, although I confess that reading it really made my eyes hurt! I’m getting too old I guess.
    Anyway, can you say something about the rat to human model? Are we really sufficiently like rats for this to apply!! Assuming that not many humans are raised in isolation what might your study tell us, if anything, about the causes of anxiety? I’ve been impressed by your excellent work on the program. Keep this up!

    • From my understanding, the same chemical processes are occurring in both species. Therefore, the rat model is good for advancing our understanding of the processes occurring in humans. In regards to the isolation model, the social isolation is the equivalent of psychological, emotional and neglect stress many children experience. The same processes in the brain occur as a result of these types of stress. Hopefully, through better understanding of the processes, scientists will be able to find a safer and more focused way to treat anxiety and depression cause by early-life stress. Thanks for the comment–Adam

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