Schulz Lab

The Schulz Lab (Kalynn Schulz, PI) is interested in how environmental events shape the developing nervous system and adult behavior. In particular, we use rodent models to investigate the mechanisms by which developmental stress exposure and deviations in pubertal timing confer risk for mental illness.

Two primary lines of research:

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1. The effects of developmental stress exposure:

The prenatal period and adolescence are two phases of development consistently linked with adult psychiatric illness. For example, when a woman experiences extreme stress during pregnancy, her offspring have an increased risk for psychiatric problems such as anxiety, depression, and schizophrenia[1-3]. In contrast, adolescence is the time when many psychiatric illnesses tend to emerge[4]. However, the relationship between adolescent development and psychiatric illness remains poorly understood. Therefore, we aim to understand how the timing of stress exposure across development determines brain and behavioral development.

2. Organizing actions of gonadal steroid hormones on brain and behavioral development:

Pubertal timing varies widely between individuals, and whether individuals undergo pubertal development early or late relative to their peers increases risk for mental illness [5]. In general, late maturing boys and early maturing girls are at greatest increased risk for psychopathologies such as depression[6-9] disordered eating[10, 11], substance abuse[12], and disruptive behavioral disorder[13].

Scientific explanations of the relationship between pubertal timing and mental illness have primarily focused on the social and emotional consequences of off-time pubertal development relative to one’s peers in boys and girls. However, pubertal gonadal steroid hormones also alter the trajectory of brain development during adolescence. We’ve recently proposed a biological model in which nervous system sensitivity to gonadal steroid hormones decreases across adolescent development [14-16]. In this framework, the developing adolescent brain is a moving target for the effects of gonadal steroid hormones, and shifts in pubertal timing may alter the course of brain development toward increased vulnerability.

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Neural mechanisms: Nicotinic Acetylcholine Receptors (nAChRs) and Mental Illness

Structure of  nicotinic acetylcholine receptors (nAChRs).

Structure of  nicotinic acetylcholine receptors (nAChRs).

Nicotinic receptor dysfunction is common across many mental illnesses[5, 6]. Nicotine activates nicotinic acetylcholine receptors in the same way as the endogenous neurotransmitter acetylcholine. Rates of smoking are significantly higher amongst depressed, anxious, and schizophrenic individuals compared to the general population[7], suggesting individuals may be “self-medicating” to alleviate some of their symptoms. In support of this possibility, nicotine has anxiolytic actions in humans[7], and nicotine also ameliorates sensory gating attentional deficits in schizophrenia patients[8]. There are several nicotinic receptor subtypes, and the two most widely found in the brain and implicated in psychiatric disorders are the high affinity nicotinic alpha4 beta2 receptors and the low affinity nicotinic alpha7 receptors[9]. Animal studies demonstrate that alpha7 or alpha4 beta2 nicotinic receptor activation facilitates memory performance in a variety of testing paradigms[10, 11]. There is also evidence to suggest that disrupting the balance of hippocampal alpha7 and alpha4 beta2 receptor activity alters memory function in rats[10, 11]. In addition, both alpha7 and alpha4 beta2 hippocampal receptors have been shown to influence anxiety and depressive-like behaviors in rodents[12]. Taken together, these data suggest that alpha7 and alpha4 beta2 nicotinic receptors in the hippocampus play a key role in both cognitive and affective behavioral function.

Representative coronal section depicting a-BTX binding in the hippocampus of a rat. a-BTX selectively binds to alpha7 nAChRs, allowing for quantification of alpha7 receptors in the brain.

Representative coronal section depicting a-BTX binding in the hippocampus of a rat. a-BTX selectively binds to alpha7 nAChRs, allowing for quantification of alpha7 receptors in the brain.

Representative coronal section depicting epibatadine binding in the hippocampus of a rat. Epibatadine selectively binds to alpha4 beta2 nAChRs, allowing for quantification of these receptors in the brain.

Representative coronal section depicting epibatadine binding in the hippocampus of a rat. Epibatadine selectively binds to alpha4 beta2 nAChRs, allowing for quantification of these receptors in the brain.

Recent lab studies: 

Behavioral effects of prenatal stress

Prenatal stress has wide-ranging effects on the behavior of rodents. Dozens of published papers demonstrate that prenatal stress increases anxiety and depressive-related behaviors, and decrease memory function. Interestingly, these effects tend to be sexually dimorphic in nature. In our laboratory, we observe prenatal stress-induced increases in anxiety-related behaviors in females but not in males, and decreased memory function in males but not in females[13]. 

Adapted from Schulz et al. 2011. Prenatal stress has sex-specific effects on the behavior of rodents in adulthood. For anxiety-related behavior in the elevated zero, prenatal stress increases anxiety (as indexed by decreased time in open areas of the zero maze) in females but not in males. In contrast, memory performance (assessed via novel object task)  is impaired in males but not females.

Adapted from Schulz et al. 2011. Prenatal stress has sex-specific effects on the behavior of rodents in adulthood. For anxiety-related behavior in the elevated zero, prenatal stress increases anxiety (as indexed by decreased time in open areas of the zero maze) in females but not in males. In contrast, memory performance (assessed via novel object task)  is impaired in males but not females.

We assess anxiety-related behaviors using the elevated zero maze. There are open and closed areas of the zero. The open areas are anxiety-provoking for rodents. As such, more time in the open area = decreased anxiety.

We assess anxiety-related behaviors using the elevated zero maze. There are open and closed areas of the zero. The open areas are anxiety-provoking for rodents. As such, more time in the open area = decreased anxiety.

We use a spatial variant of the novel object recognition task to assess memory function. A rat is placed into an arena with two identical objects, allowed to explore for 5 min, and then returned to the home cage. One hour later, the rat is placed back into the test arena with the same objects, but one of the objects has changed locations within the arena. Rats have a natural interest in novelty, so if the rat remembers the previous spatial configuration of objects, he/she will investigate the object in a new locataion more than the object in the stationary location. If a rat explores both object locations equally, this suggests it doesn't remember the original spatial location.

We use a spatial variant of the novel object recognition task to assess memory function. A rat is placed into an arena with two identical objects, allowed to explore for 5 min, and then returned to the home cage. One hour later, the rat is placed back into the test arena with the same objects, but one of the objects has changed locations within the arena. Rats have a natural interest in novelty, so if the rat remembers the previous spatial configuration of objects, he/she will investigate the object in a new locataion more than the object in the stationary location. If a rat explores both object locations equally, this suggests it doesn't remember the original spatial location.

Choline as a Stress Intervention

Choline is an essential nutrient and an important structural component of all cell membranes. Therefore, a women's need for choline increases during pregnacy because the fetus requires high choline levels to build new cells. Although choline is abundant in protein-rich foods such as eggs, meats, and beans, about 25% of women do not meet the recommended levels of choline during pregnancy[14], and are consequently at a 4-fold greater risk of having a child with neural tube defects. Interestingly, choline is also a neurotransmitter in the brain and acts directly on the nAChRs that are altered by prenatal stress. As such, we tested whether perinatal dietary choline supplementation counteracts the detrimental effects of prenatal stress. Specifically, we fed stressed and nonstressed dams a choline-supplemented or control diet during pregnancy and lactation, and measured anxiety-related behaviors in adulthood.

Pregnant dams experienced stress procedures during the last week of gestation, or were left undisturbed (control). Half of all stressed and nonstressed dams were fed a choline-supplemented diet during pregnancy and through lactation (postnatal day 21), whereas the other half of dams were fed control chow (normative choline levels). Offspring were weaned at 21 days of age, and all animals were fed the control chow for the remainder of the experiment. In adulthood, animals were tested for anxiety-related behavior in the elevated zero maze, and memory function using the novel object recognition task.

Pregnant dams experienced stress procedures during the last week of gestation, or were left undisturbed (control). Half of all stressed and nonstressed dams were fed a choline-supplemented diet during pregnancy and through lactation (postnatal day 21), whereas the other half of dams were fed control chow (normative choline levels). Offspring were weaned at 21 days of age, and all animals were fed the control chow for the remainder of the experiment. In adulthood, animals were tested for anxiety-related behavior in the elevated zero maze, and memory function using the novel object recognition task.

Adapted from Schulz et al., 2013, Behavioural Brain Research. The effects of prenatal stress (PS) and perinatal choline on female anxiety-related behaviors and male spatial memory. (A) Perinatal choline supplementation ameliorates the effects of PS on adult anxiety-related behaviors in females but not males (male data not shown). (B) Perinatal choline supplementation ameliorates the effects of PS on adult spatial memory function in adult males but not females (female data not shown).

Adapted from Schulz et al., 2013, Behavioural Brain Research. The effects of prenatal stress (PS) and perinatal choline on female anxiety-related behaviors and male spatial memory. (A) Perinatal choline supplementation ameliorates the effects of PS on adult anxiety-related behaviors in females but not males (male data not shown). (B) Perinatal choline supplementation ameliorates the effects of PS on adult spatial memory function in adult males but not females (female data not shown).

Current Projects

Determining whether adolescence is a discrete sensitive period for the organizing actions of gonadal steroid hormones on cognitive and emotional behavioral function.

Does dietary choline protect against the deleterious effects of adolescent stress on adult behavior?

Determining the effects of prenatal stress and perinatal dietary choline on brain AChR levels.

Refererences

1.           Walker, E., V. Mittal, and K. Tessner, Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annual Review of Clinical Psychology, 2008. 4: p. 189-216.

2.           Walker, E., et al., Schizophrenia: Etiology and course. Annual Review of Psychology, 2004. 55: p. 401-430.

3.           Walker, E.F., Z. Sabuwalla, and R. Huot, Pubertal neuromaturation, stress sensitivity, and psychopathology. Development and Psychopathology, 2004. 16(4): p. 807-824.

4.           Steinberg, L., et al., The study of developmental psychopathology in adolescence: integrating affective neuroscience with the study of context, in Handbook of Developmental Psychopathology, D. Cicchetti, Editor. 2005, John Wiley & Sons: New York, NY.

5.           Graber, J.A., Pubertal timing and the development of psychopathology in adolescence and beyond. Hormones and Behavior, 2013. 64(2): p. 262-269.

6.           Copeland, W., et al., Outcomes of Early Pubertal Timing in Young Women: A Prospective Population-Based Study. American Journal of Psychiatry, 2010. 167(10): p. 1218-1225.

7.           Graber, J.A., et al., Is psychopathology associated with the timing of pubertal development? Journal of the American Academy of Child and Adolescent Psychiatry, 1997. 36(12): p. 1768-1776.

8.           Graber, J.A., Pubertal and neuroendocrine development and risk for depression. Adolescent Emotional Development and the Emergence of Depressive Disorders, 2008: p. 74-91.

9.           Negriff, S. and E.J. Susman, Pubertal Timing, Depression, and Externalizing Problems: A Framework, Review, and Examination of Gender Differences. Journal of Research on Adolescence, 2011. 21(3): p. 717-746.

10.         Zehr, J.L., et al., An association of early puberty with disordered eating and anxiety in a population of undergraduate women and men. Hormones and Behavior, 2007. 52(4): 427-35

11.         Klump, K.L., Puberty as a critical risk period for eating disorders: A review of human and animal studies. Hormones and Behavior, 2013. 64(2): p. 399-410.

12.         Andersson, T. and D. Magnusson, BIOLOGICAL MATURATION IN ADOLESCENCE AND THE DEVELOPMENT OF DRINKING HABITS AND ALCOHOL-ABUSE AMONG YOUNG MALES - A PROSPECTIVE LONGITUDINAL-STUDY. Journal of Youth and Adolescence, 1990. 19(1): p. 33-41.

13.         Graber, J.A., et al., Is pubertal timing associated with psychopathology in young adulthood? Journal of the American Academy of Child and Adolescent Psychiatry, 2004. 43(6): p. 718-726.

14.         Schulz, K.M. and C.L. Sisk, Gonadal hormonal influences on the adolescent brain and trajectories of behavioral development, in Hormones Brain and Behavior, 2016. Academic Press: San Diego CA.

15.         Schulz, K.M. and C.L. Sisk, The organizing actions of adolescent gonadal steroid hormones on brain and behavioral development. Neuroscience and Biobehavioral Reviews, 2016. 70: p. 148-158.

16.         Schulz, K.M., H.A. Molenda-Figueira, and C.L. Sisk, Back to the future: The organizational-activational hypothesis adapted to puberty and adolescence. Horm Behav, 2009. 55(5): p. 597-604.

17.         Newhouse, P., A. Singh, and A. Potter, Nicotine and nicotinic receptor involvement in neuropsychiatric disorders. Current Topics in Medicinal Chemistry, 2004. 4(3): p. 267-282.

18.         Singh, A., A. Potter, and P. Newhouse, Nicotinic acetylcholine receptor system and neuropsychiatric disorders. Idrugs, 2004. 7(12): p. 1096-1103.

19.         Araki, H., K. Suemaru, and Y. Gomita, Neuronal nicotinic receptor and psychiatric disorders: Functional and behavioral effects of nicotine. Japanese Journal of Pharmacology, 2002. 88(2): p. 133-138.

20.         Martin, L.F. and R. Freedman, Schizophrenia and the alpha 7 nicotinic acetylcholine receptor, in Integrating the Neurobiology of Schizophrenia. 2007. p. 225-246.

21.         Adams, C.E. and K.E. Stevens, Evidence for a role of nicotinic acetylcholine receptors in schizophrenia. Frontiers in Bioscience, 2007. 12: p. 4755-4772.

22.         Graef, S., et al., Cholinergic receptor subtypes and their role in cognition, emotion, and vigilance control: An overview of preclinical and clinical findings. Psychopharmacology, 2011. 215(2): p. 205-229.

23.         Levin, E.D., F.J. McClernon, and A.H. Rezvani, Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology, 2006. 184(3-4): p. 523-539.

24.         Mineur, Y.S. and M.R. Picciotto, Nicotine receptors and depression: revisiting and revising the cholinergic hypothesis. Trends in Pharmacological Sciences, 2010. 31(12): p. 580-586.