Elsevier

Neuroscience

Volume 144, Issue 1, 5 January 2007, Pages 26-37
Neuroscience

Behavioural neuroscience
Estrogen modulates learning in female rats by acting directly at distinct memory systems

https://doi.org/10.1016/j.neuroscience.2006.09.002Get rights and content

Abstract

Physiologically high levels of circulating estradiol enhance the use of place learning and impair the use of response learning to find food on a land maze. These two types of learning are impaired by lesions of distinct neuronal structures, i.e. the hippocampus and striatum, respectively. Moreover, it has been shown in male rats that compromising hippocampal function can promote the use of response learning, while compromising striatal function can promote place learning. These findings suggest an ongoing competition between the hippocampus and striatum during cognition, such that intact functioning of one structure somehow obstructs the relative participation of the other. The goal of this study was to determine if estrogen’s opposing effects on place and response learning in female rats are due to direct actions, either independent or interacting, at the hippocampus and striatum. We infused 0.5 μM 17β-estradiol 3-sulfate sodium or vehicle bilaterally into the dorsal hippocampus or dorsolateral striatum of ovariectomized young adult female rats, 48, 24 and 2 h before training. Rats were tested on one of three appetitive tasks in a Y-maze: place learning, response learning, or response learning with reduced visual cues (cue-poor condition). Intrahippocampal estradiol infusions enhanced place learning, reversing a cannula-induced impairment, whereas intrastriatal infusions had no effects on place learning. Estradiol infusions into neither structure significantly affected response learning when extramaze cues were visible. However, in the response task, cue-poor condition, intrastriatal but not intrahippocampal infusions impaired learning. These data demonstrate that estrogen modulates place and response learning at the hippocampus and striatum respectively, most likely through independent actions at these two structures.

Section snippets

Subjects

Three-month-old Sprague–Dawley virgin, female rats were obtained from Harlan (Oregon, WI, USA barrier) in squads of 10–12 rats. Rats were housed individually in plastic cages with free access to food and water until food restriction was initiated. Lights were maintained on a 12-h light/dark cycle. Rats were given at least one week to habituate to the vivarium before any procedures were initiated.

All rats underwent bilateral ovariectomy 21 days prior to behavioral training. They were allowed

Results

Rats included in the final analyses showed typical diestrous vaginal smears of ovariectomized rats for five days prior to training (data not shown), indicating a lack of estrous cycles.

Discussion

Our findings suggest that estrogen acts at distinct neural sites to modulate performance on two maze tasks that differ in the cognitive strategy required for successful completion. Specifically, hormone injections into the hippocampus but not striatum of ovariectomized rats enhanced place learning, a task requiring the use of extramaze cues to find a food reward. The enhancement following intrahippocampal estrogen treatment reflected a reversal of impairment caused by cannula implantation.

Conclusions

Our findings suggest that estrogen’s effects on place and response learning result from independent actions at the hippocampus and striatum, respectively. The enhancement of place learning is supported by a broad literature reporting many effects of estrogen on the neurochemistry and physiology of the hippocampal system. The neural mechanisms that underlie the impairment of response learning are less clear, but may relate to downstream consequences in the striatum of estrogen-induced modulation

Acknowledgments

Supported by NSF IBN 0081061, IOB 0520876, and NIH/HD07333.

References (88)

  • J.M. Daniel et al.

    Estrogen enhances performance of female rats during acquisition of a radial arm maze

    Horm Behav

    (1997)
  • J.M. Daniel et al.

    Estrogen replacement in ovariectomized rats affects strategy selection in the Morris water maze

    Neurobiol Learn Mem

    (2004)
  • J.M. Daniel et al.

    Estrogen increases the sensitivity of ovariectomized rats to the disruptive effects produced by the antagonism of D2 but not D1 dopamine receptors during performance of a response learning task

    Horm Behav

    (2006)
  • M. Day et al.

    Ovariectomy-induced disruption of long-term synaptic depression in the hippocampal CA1 region in vivo is attenuated with chronic estrogen replacement

    Neurobiol Learn Mem

    (2005)
  • G.P. Dohanich

    Gonadal steroids, learning and memory

  • H.E. Edwards et al.

    Steroid hormones affect limbic afterdischarge thresholds and kindling rates in adult female rats

    Brain Res

    (1999)
  • C. Euvrard et al.

    Effect of estrogen on changes in the activity of striatal cholinergic neurons induced by DA drugs

    Brain Res

    (1979)
  • A.J. Fader et al.

    Estrogen improves performance of reinforced T-maze alternation and prevents the amnestic effects of scopolamine administered systemically or intrahippocampally

    Neurobiol Learn Mem

    (1998)
  • A.J. Fader et al.

    Estrogen improves working but not reference memory and prevents amnestic effects of scopolamine of a radial-arm maze

    Pharmacol Biochem Behav

    (1999)
  • P. Falardeau et al.

    Regional effect of estradiol on rat caudate-putamen dopamine receptors: lateral-medial differences

    Neurosci Lett

    (1987)
  • L.A. Galea et al.

    High levels of estradiol disrupt conditioned place preference learning, stimulus response learning and reference memory but have limited effects on working memory

    Behav Brain Res

    (2001)
  • R.B. Gibbs

    Estrogen replacement enhances acquisition of a spatial memory task and reduces deficits associated with hippocampal muscarinic receptor inhibition

    Horm Behav

    (1999)
  • R.B. Gibbs

    Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats

    Neurobiol Aging

    (2000)
  • R.B. Gibbs et al.

    Effects of raloxifene and estradiol on hippocampal acetylcholine release and spatial learning in the rat

    Psychoneuroendocrinology

    (2004)
  • R.B. Gibbs et al.

    Effects of estrogen on potassium-stimulated acetylcholine release in the hippocampus and overlying cortex of adult rats

    Brain Res

    (1997)
  • W.R. Harrington et al.

    Activities of estrogen receptor α- and β-selective ligands at diverse estrogen responsive gene sites mediating transactivation or transrepression

    Mol Cell Endocrinol

    (2003)
  • D.A. Johnson et al.

    The effect of steroid sulfatase inhibition on learning and spatial memory

    Brain Res

    (2000)
  • B. Kolb et al.

    Dissociation of the contributions of the prefrontal cortex and dorsomedial thalamic nucleus to spatially guided behavior in the rat

    Behav Brain Res

    (1982)
  • D.L. Korol

    Role of estrogen in balancing contributions from multiple memory systems

    Neurobiol Learn Mem

    (2004)
  • D.L. Korol et al.

    Shifts in preferred learning strategy across the estrous cycle in female rats

    Horm Behav

    (2004)
  • V.N. Luine

    Estradiol increases choline acetyltransferase activity in specific basal forebrain nuclei and projection areas of female rats

    Exp Neurol

    (1985)
  • V.N. Luine et al.

    Estradiol enhances learning and memory in a spatial memory task and effects levels of monoaminergic neurotransmitters

    Horm Behav

    (1998)
  • L.K. Marriott et al.

    Short-term estrogen treatment in ovariectomized rats augments hippocampal acetylcholine release during place learning

    Neurobiol Learn Mem

    (2003)
  • R.J. McDonald et al.

    Parallel information processing in the water maze: evidence for independent memory systems involving dorsal striatum and hippocampus

    Behav Neural Biol

    (1994)
  • E. Miyoshi et al.

    Impaired learning in a spatial working memory version and in a cued version of the water maze in rats with MPTP-induced mesencephalic dopaminergic lesions

    Brain Res Bull

    (2002)
  • S.J. Mizumori et al.

    Parallel processing across neural systems: implications for a multiple memory system hypothesis

    Neurobiol Learn Mem

    (2004)
  • M.G. Packard et al.

    Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning

    Neurobiol Learn Mem

    (1996)
  • M.G. Packard et al.

    Posttraining estradiol injections enhance memory in ovariectomized rats: cholinergic blockade and synergism

    Neurobiol Learn Mem

    (1997)
  • M.G. Packard et al.

    Amygdala modulation of multiple memory systems: hippocampus and caudate-putamen

    Neurobiol Learn Mem

    (1998)
  • E.J. Roy et al.

    Estradiol in the striatum: effects on behavior and dopamine receptors but no evidence for membrane steroid receptors

    Brain Res Bull

    (1990)
  • M.C. Saleh et al.

    Autonomic and cardiovascular reflex responses to central estrogen injection in ovariectomized female rats

    Brain Res

    (2000)
  • J.W. Simpkins et al.

    Role of estrogen replacement therapy in memory enhancement and the prevention of neuronal loss associated with Alzheimer’s Disease

    Am J Med

    (1997)
  • M. Singh et al.

    Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats

    Brain Res

    (1994)
  • J. Tropp et al.

    Sex differences in the dynamics of cue utilization and exploratory behavior

    Behav Brain Res

    (2001)
  • Cited by (130)

    • Beyond sex and gender differences: The case for women's health research

      2023, Principles of Gender-Specific Medicine: Sex and Gender-Specific Biology in the Postgenomic Era
    • Hippocampus-sensitive and striatum-sensitive learning one month after morphine or cocaine exposure in male rats

      2022, Pharmacology Biochemistry and Behavior
      Citation Excerpt :

      A third set of rats was trained on a dual solution T-maze in which either place or response strategies afford effective solutions; probe tests administered after dual-solution training identify the dominant strategy used on the task (Restle, 1957; Tolman et al., 1946). These tasks have been used reliably to reveal changes across multiple memory system functions resulting from extensive training, advanced age, stress, and hormone status (e.g., Gardner et al., 2013, 2016, 2020a, 2020b; Gold et al., 2013; Gold, 2016; Hawley et al., 2012; Korol and Pisani, 2015; Korol and Wang, 2018; Packard and Goodman, 2012, 2013; Packard et al., 2018; Packard and McGaugh, 1996; Schwabe, 2013; Zurkovsky et al., 2007). Additional experiments measured tissue levels of glial fibrillary acidic protein (GFAP), brain-derived neurotrophic factor (BDNF), and glycogen synthase kinase-3 beta (GSK3β) across brain regions one month after cocaine or morphine exposure.

    • Influence of ovarian hormones on value-based decision-making systems: Contribution to sexual dimorphisms in mental disorders

      2021, Frontiers in Neuroendocrinology
      Citation Excerpt :

      Reinforcement learning paradigms in animals have been based on appropriate responses (correct physical turn towards reward) and place learning (physical reward placement in the environment) for rewards and associated with brain structures, such as dorsal striatum for response learning and hippocampus for place learning (Shelton et al., 2013). Experiments with response learning in normally cycling and ovariectomized rats have demonstrated that direct administration of estradiol to the dorsal striatum impaired response learning (Davis et al., 2005; Zurkovsky et al., 2007; Wang et al., 2008). Combined with a D2-receptor antagonist but not D1-receptor antagonist, chronic estradiol treatment of ovariectomized rats resulted in increased response learning error rates (Daniel et al., 2006).

    View all citing articles on Scopus
    View full text