**4. Estrogen and the aging brain**

One of the most interesting research fields in women's health of the last decade includes the growing appreciation that estrogen plays relevant neurotrophic and neuroprotective roles during adulthood. This amplifies the relevance of the potential impact of the prolonged post-menopausal hypoestrogenic state on learning and memory processes and the potential increased vulnerability of ageing women to brain injury and neurodegenerative diseases. The longer female life expectancy has implied that nowadays women live one-third of their lives beyond ending of their ovarian function, increasing the need for new therapeutic strategies to facilitate successful aging (defined as low probability of disease), high cognitive and physical abilities, and active engagement in life. Taking into account that changes in the ageing nervous system are subtle, they could be reversed and cognitive performance may be improved by pharmacological treatments.

The ematic concentration of estrogens decreases with age and the post-menopause low values of estrogens are often followed by an acceleration of the age effects on cognition. Cognitive decline during aging affect memory abilities, attention, and speed of information processing (Sherwin & Henry, 2008).

Even though several cognitive functions seem to be unaltered in normal aging, age-related impairments are mainly evident in tasks implying free or cued recall or WM (Small et al, 1999). Although verbal memory has been reported to be the cognitive function most deeply affected with increasing age (Marquis et al, 2002; Rabbitt & Lowe, 2000) other cognitive domains such as attention (Stankov, 1988) visual perception, and verbal fluency (Ashman, 1999) are also influenced. Thus, the attempt to delay or prevent the cognitive impairment occurring with normal aging is an important goal to protect the quality of life for women during the latter one third of their lifespan. Because ERs are present in both the HF and frontal lobes which subserve verbal memory, WM and retrieval, we can hypothesize that estrogen might play an important protective role against the decline in these cognitive functions, occurring with normal aging. Therefore, researchers have tried to verify if the estrogen administration to women at the beginning or during menopause would protect against cognitive impairments that normally take place with increasing age.

During the past few decades, data from basic neuroscience and from animal and human studies have suggested that ERT given to postmenopausal women might protect against specific cognitive declines occurring with normal aging. On the other hand, the numerous inconsistencies in this body of evidence point to the possibility that there are contingencies which modify the supposed neuroprotective effects of ERT on cognitive aging (Sherwin & Henry, 2008).

Estrogen Influences on Cognition 175

[4] Amin Z, Mason GF, Cavus I, Krystal JH, Rothman DL, Epperson CN. The interaction of

[5] Ashman TA, Mohs RC, Harvey PD. Cognition and aging. In: Principles of geriatric

Hatter JB, Ouslander JG (Eds), New York: McGraw-Hill, 1999; 1219–1228.

[8] Badre D, Wagner AD. Left ventrolateral prefrontal cortex and the cognitive control of

[9] Berman KF et al. Modulation of cognition-specific cortical activity by gonadal steroids: a

[10] Berry B, McMahan R, Gallagher M. Spatial learning and memory at defined points of

[11] Bertrand PP, Paranavitane UT, Chavez C, Gogos A, Jones M, van den Buuse M. The

[12] Bimonte HA, Denenberg VH. Estradiol facilitates performance as working memory

[13] Bixo M, Bäckström T, Winblad B, Andersson, A. Estradiol and testosterone in specific

[14] Blair RJ, Morris JS, Frith CD, Perrett DI, Dolan RJ. Dissociable neural responses to

[15] Bowman RE, Zrull MC, Luine VN. Chronic restraint stress enhances radial arm maze

[16] Bryant DN, Sheldahl LC, Marriott LK, Shapiro RA, Dorsa DM. Multiple pathways transmit neuroprotective effects of gonadal steroids. Endocrinology. 2006; 29: 199–207. [17] Carr, B.R. Disorders of the ovaries and female reproductive tract. In: Wilson, J.D;

[18] Clark, JH; Schrader, WT; O'Malley, BW; Mechanisms of action of steroid hormones, In:

[19] Clarke CH, Norfleet AM, Clarke MSF, Watson CS, Cunningham KA, Thomas ML

[21] Daniel JM, Dohanich GP. Acetylcholine mediates the estrogen induced in crease in

[23] Daniel JM. Effects of oestrogen on cognition: what have we learned from basic

neuropsychiatric disorders. Climateric. 2007; 10 (Suppl 2): 97–104.

improvement in working memory. J. Neurosci. 2001; 21: 6949–6956. [22] Daniel JM, Fader AJ, Spencer AL, Dohanich GP. Estrogen enhances performance of

research? J Neuroendocrinol. 2006; 18: 787-795.

load increases. Psychoneuroendocrinology. 1999; 24: 161-173.

facial expressions of sadness and anger. Brain. 1999; 122: 883–893.

performance in female rats. Brain Res. 2001; 904: 279–289.

Endocrinology, W.B. Saunders, Philadelphia, 1998; 751–773.

in women. Pharmacol. Biochem. Behav. 2006; 84: 635-643.

[6] Baddeley A. Working memory. C. R. Acad. Sci. III. 1998; 321: 167-173.

memory. Neuropsychologia. 2007; 45 (13): 2883-901.

[7] Baddeley A. Working memory. Science. 1992; 255:556-559.

94: 8836–8841.

Neurosci. 1997; 11: 267–274.

Mol. Biol. 1995; 55: 297–303.

Philadelphia, 1992; 35–90.

neuroactive steroids and GABA in the development of neuropsychiatric disorders

medicine and gerontology (4th edition). Hazzard WR, Blass JP, Ettinger WH,

positron-emission tomography study in women, Proc. Natl. Acad. Sci. USA. 1997;

the estrous cycle: effects on performance of a hippocampal-dependent task. Behav.

effect of low estrogen state on serotonin transporter function in mouse hippocampus: A behavioral and electrochemical study. Brain Res. 2005; 1064: 10-20.

regions of the human female brain in different endocrine states. J. Steroid Biochem.

Foster, D.W; Kronenberg, H.M; Larsen, P.R. (Eds.). Williams Textbook of

Wilson, J., Foster, D.W. (Eds.), Textbook of Endocrinology. W.B. Saunders,

Perimembrane localization of the estrogen receptor alpha protein in neuronal processes of cultured hippocampal neurons. Neuroendocrinology. 2000; 71: 34–42. [20] Craig MC, Murphy DG. Estrogen: effects on normal brain function and neur

NMDA receptor binding in CA1 of the hippocampus and the associated

female rats during acquisition of a radial arm maze. Horm. Behav. 1997; 32:217–225.

Even though an extensive literature on the putative neuroprotective effects of estrogen on cognitive functions in postmenopausal women is available, many discrepancies still exist. The critical period hypothesis, introduced many years ago, attempts to account for the inconsistencies in this literature by positing that ERT can have a protective effect on some aspects of cognition in older women, only when it is initiated soon after the menopause. Indeed, data from basic neuroscience and from the animal and human studies provides compelling support for the critical period hypothesis (Sherwin & Henry, 2008). Although it is not completely clarified why estrogen does not protect cognitive functions and may even cause harm when administered to women over the age of 65 years, it is possible that the typical modifications of brain aging, such as a reduction of brain volume, neuronal size, number of dendritic spines, and alterations in neurotransmitter systems form an adverse background preventing the neuroprotective effects of exogenous estrogen. Other factors that have likely contributed to the inconsistencies of the estrogen–cognition literature include differences in the estrogen agonist utilized, their route of administration, cyclic versus continuous regimens, and the concomitant administration of progestins. In conclusion, there is considerable evidence supporting the use of estrogen during the menopause and postmenopausal periods for the prevention and treatment of AD and other neurologic disorders. Nevertheless, the efficacy of estrogen requires that we take into account the most recent data on hormone neurobiology, in order to administer the hormone at the right time, with the right formulation, and to the appropriate population of women (Gleason, 2005; Simpkins & Meharvan, 2008).

#### **5. Conclusions**

Besides the mechanisms concerning the neuroprotective role of estrogen in dependence of the age of its administration, further studies are necessary to completely clarify the relative efficacy of cyclic versus continuous hormone regimens, the accessibility to the brain of various estrogen compounds, and their different routes of administration. Moreover, there are no dose response results related to estrogen and cognitive functioning in women, in spite of the increasing clinical trend for administering low doses of estrogen to postmenopausal women. The finding of a prominent dose-dependent effect of estradiol on the density of hippocampal CA1 pyramidal spine synapse in OVX rats (MacLusky et al, 2005) emphasizes the relevance of obtaining such data for women. When the optimal neurobiological and pharmacological parameters of the estrogen–cognition relationship are known, these data could be used clinically to attenuate or to prevent cognitive decline in older women, which represent the fastest growing section of the population in industrialized countries.

#### **6. References**


Even though an extensive literature on the putative neuroprotective effects of estrogen on cognitive functions in postmenopausal women is available, many discrepancies still exist. The critical period hypothesis, introduced many years ago, attempts to account for the inconsistencies in this literature by positing that ERT can have a protective effect on some aspects of cognition in older women, only when it is initiated soon after the menopause. Indeed, data from basic neuroscience and from the animal and human studies provides compelling support for the critical period hypothesis (Sherwin & Henry, 2008). Although it is not completely clarified why estrogen does not protect cognitive functions and may even cause harm when administered to women over the age of 65 years, it is possible that the typical modifications of brain aging, such as a reduction of brain volume, neuronal size, number of dendritic spines, and alterations in neurotransmitter systems form an adverse background preventing the neuroprotective effects of exogenous estrogen. Other factors that have likely contributed to the inconsistencies of the estrogen–cognition literature include differences in the estrogen agonist utilized, their route of administration, cyclic versus continuous regimens, and the concomitant administration of progestins. In conclusion, there is considerable evidence supporting the use of estrogen during the menopause and postmenopausal periods for the prevention and treatment of AD and other neurologic disorders. Nevertheless, the efficacy of estrogen requires that we take into account the most recent data on hormone neurobiology, in order to administer the hormone at the right time, with the right formulation, and to the appropriate population of women

Besides the mechanisms concerning the neuroprotective role of estrogen in dependence of the age of its administration, further studies are necessary to completely clarify the relative efficacy of cyclic versus continuous hormone regimens, the accessibility to the brain of various estrogen compounds, and their different routes of administration. Moreover, there are no dose response results related to estrogen and cognitive functioning in women, in spite of the increasing clinical trend for administering low doses of estrogen to postmenopausal women. The finding of a prominent dose-dependent effect of estradiol on the density of hippocampal CA1 pyramidal spine synapse in OVX rats (MacLusky et al, 2005) emphasizes the relevance of obtaining such data for women. When the optimal neurobiological and pharmacological parameters of the estrogen–cognition relationship are known, these data could be used clinically to attenuate or to prevent cognitive decline in older women, which represent the fastest growing section of the population in

[1] Abreu CT, Tavares MC, Marchetti A, d'Onofrio A, Gasbarri A, Tomaz C. A novel

[2] Addington J, Addington D. Facial affect recognition and information processing in schizophrenia and bipolar disorder. Schizophr. Res. 1998; 32(3): 171-81. [3] Adolphs R. Neural systems for recognizing emotion. Curr. Opin. Neurobiol. 2002; 12:

working memory test using capuchin monkey (Cebus apella) emotional faces.

(Gleason, 2005; Simpkins & Meharvan, 2008).

Neurobiologia. 2006; 69: 267-274.

**5. Conclusions** 

industrialized countries.

169-177.

**6. References** 


Estrogen Influences on Cognition 177

[42] Gasbarri A, Pompili A, d'Onofrio A, Cifariello A, Tavares MC, Tomaz C. Working

[43] Gasbarri A., Pompili A., Tavares M.C, Tomaz, C. Estrogen and cognitive functions.

[44] Genazzani AR, Monteleone P, Gambacciani M. Hormonal influence on the central

[45] Genazzani AR, Pluchino N, Luisi S, Luisi M. Estrogen, cognition and female ageing.

[46] Gibbs RB, Aggarwal P. Estrogen and basal forebrain cholinergic neurons: Implications

[47] Gibbs RB, Gabor R, Cox T, Johnson DA. Effects of raloxifene and estradiol on

[48] Gibbs RB, Jognson DA. Sex-specific effects of gonadectomy and hormone treatment on

[49] Gleason CE, Carlsson CM, Johnson S, Atwood C, Asthana S. Clinical pharmacology

[50] Gotham AM, Brown RG, Marsden CP. "Frontal" cognitive function in patients with Parkinson's disease "on" and "off" levodopa. Brain. 1988; 111: 299–321. [51] Grady CL, Craik FIM. Changes in memory processing with age. Curr. Opin.

[52] Gresack JE, Kerr KM, Frick KM. Short-term environmental enrichment decreases the

[53] Gruber CJ, Tschugguel W, Schneeberger C and Huber JC Production and actions of

[54] Gulinello M, Lebesgue D, Jover-Mengual T, Zukin RS, Etgen AM. Acute and chronic

[55] Hao J, Rapp PR, Janssen WG et al. Interactive effects of age and estrogen on cognition

[56] Hart SA, Patton JD, Woolley CS. Quantitative analysis of ER alpha and GAD

[57] Hart SA, Snyder MA, Smejkalova T, Woolley CS. Estrogen mobilizes a subset of

[58] Hasselmo ME. The role of acetylcholine in learning and memory. Curr. Opin.

[59] Henderson, V W. Aging, Estrogens, and Episodic Memory in Women. Cogn Behav

[60] Henderson, V W. Action of estrogens in the aging brain: Dementia and cognitive

for brain aging and Alzheimer's disease-related cognitive decline. Horm. Behav.

hippocampal acetylcholine release and spatial learning in the rat.

acquisition of 12-arm radial maze task by Sprague Dawley rats. Endocrinology.

and differential cognitive efficacy of estrogen preparations. Ann N Y Acad Sci.

mnemonic response to estrogen in young, but not aged female mice. Brain Res.

estradiol treatments reduce memory deficits induced by transient global ischemia

and pyramidal neurons in monkey prefrontal cortex. Proc. Natl. Acad. Sci. U. S. A.

colocalization in the hippocampus of the adult female rat. J. Comp. Neurol. 2001;

estrogen receptor-alpha-immunoreactive vesicles in inhibitory presynaptic boutons

Expert review of endocrinology & metabolism. 2009; 4: 507-520.

nervous system. Maturitas.2002; 43 (Suppl. 1): S11–S17.

Psychoneuroendocrinology . 2008; 33 (7): 964-72.

Hum. Reprod. Update. 2007; 13: 175-87.

Psychoneuroendocrinology 2004; 29: 741-748.

estrogens. N. Engl. J. Med. 2002; 346: 340–352.

in female rats. Horm. Behav. 2006; 49: 246–260.

in hippocampal CA1. J. Neurosci. 2007; 27: 2102-2111.

aging. Biochimica et Biophysica Acta, 2010; 1800: 1077–1083.

1998; 34: 98-111.

2008; 149 (6): 3176-83.

2005; 1052: 93-115.

2007; 1160: 91–101.

2007; 104: 11465-11470.

Neurobiol. 2006; 16: 710-5.

Neurol., 2009; 22 (4): 205–214.

440 (2): 144-155.

Neurobiol. 2000; 10: 224–231.

memory for emotional facial expressions: role of the estrogen in young women.


[24] Davis DM, Jacobson TK, Aliakbari S, Mizumori SJ. Differential effects of estrogen on

[25] Dohanich GP. Gonadal steroids, learning and memory. In: Hormones, Brain and

[26] Duff SJ, Hampson E. A beneficial effect of estrogen on working memory in

[27] Dumas J, Hancur-Bucci C, Naylor M, Sites C, Newhouse P. Estrogen treatment effects

[28] Ekman P, Friesen WV. Constants across cultures in the face and emotion. J. Pers. Soc.

[30] Englemann M, Ebner K, Landgraf R, Wotjak CT. Effects of Morris water maze testing

[32] Fader AJ, Johnson PE, Dohanich GP. Estrogen improves working but not reference

[33] Farhat, MY; Lavigne, MC; Ramwell, PW. The vascular protective effects of estrogen.

[34] Fernandez SM, Frick KM. Chronic oral estrogen affects memory and neurochemistry in

[35] Fragaszy DM, Visalberghi E, Fedigan LM. The Complete Capuchin: The Biology of the

[36] Frick KM, Berger-Sweeney J. Spatial reference memory and neocortical neurochemistry vary with the estrous cycle in C57Bl 6 mice. Behav. Neurosci. 2001; 115: 229–237. [37] Frick KM, Fernandez SM, Bennett JC, Prange-Kiel J, Maclusky NJ, Leranth CS.

[38] Frick KM, Fernandez SM, Bulinski SC. Estrogen replacement improves spatial

[39] Frye CA, Duffy CA, Walf AA. Estrogens and progestins enhance spatial learning of

[40] Frye CA. Estrus-associated decrements in a water maze task are limited to acquisition.

[41] Funahashi S, Chafee MV, Goldman-Rakic PS. Prefrontal neuronal activity in rhesus monkeys performing a delayed anti-saccade task. Nature. 1993; 365: 753–756.

Behavioral training interferes with the ability of gonadal hormones to increase CA1 spine synapse density in ovariectomized female rats. Eur. J. Neurosci. 2004; 19: 1–7.

reference memory and increases hippocampal synaptophysin in aged female mice.

intact and ovariectomized rats in the object placement task. Neurobiol. Learn.

middle-aged female mice. Behav. Neurosci. 2004; 118: 1340–1351.

genus Cebus. Cambridge: Cambridge University Press. 2004.

vasopressin and oxytocin in the rat. Horm. Behav. 2006; 50: 496–501. [31] Ennaceur A, Neave N, Aggleton JP. Spontaneous object recognition and object location

women. Neuropsychopharmacology. 2006; 31: 2065–2078.

[29] Ekman P. Facial expression and emotion. Am. Psychol. 1993; 48 (4): 384-92.

Diego, CA: Academic Press. 2002; 265–327.

Pharmacol. Biochem. Behav. 1999; 62: 711–717.

132–137.

38: 262-276.

509–519.

Psychol. 1971; 17: 124-129.

Faseb J. 1996; 10: 615–624.

Neuroscience. 2002; 115: 547–558.

Mem. 2007; 88: 208–216.

Physiol. Behav. 1995; 57: 5–14.

hippocampal- and striatal-dependent learning. Neurobiol. Learn. Mem. 2005; 84:

Behavior. Pfaff DW, Arnold AP, Etgen AM, Fahrbach SE, Rubin RI (Eds), San

ostmenopausal women taking hormone replacement therapy. Horm. Behav. 2000;

on anticholinergic-induced cognitive dysfunction in normal postmenopausal

on the neuroendocrine stress response and intra hypothalamic release of

memory in rats: the effects of lesions in the cingulated cortices, the medial prefrontal cortex, the cingulum bundle and the fornix. Exp. Brain. Res. 1997; 113:

memory and prevents amnestic effects of scopolamine of a radial-arm maze.


Estrogen Influences on Cognition 179

[78] Li C et al. Estrogen alters hippocampal dendritic spine shape and enhances synaptic

[79] Liu F, Day M, Muniz LC et al. Activation of estrogen receptor beta regulates

[80] Luciana M, Depue RA, Arbisi P, Leon A. Facilitation of working memory in humans by

[81] Luine V, Richards ST, Wu VY, Beck K. Estradiol enhances learning and memory in a

[82] Luine VN. The prefrontal cortex, gonadal hormones and memory. Horm. Behav. 2007;

[83] Luine, VN. Sex steroids and cognitive function. J. Neuroendocrinol., 2008; 20: 866-872. [84] MacLusky NJ, Luine VN, Hajszan T, Leranth C. The 17 a and b isomers of estradiol

[85] Maki PM, Resnick SM. Longitudinal effects of estrogen replacement therapy on PET cerebral blood flow and cognition. Neurobiol. Aging. 2000; 21 (2): 373-83. [86] Maki PM, Rich JB, Rosenbaum RS. Implicit memory varies across the menstrual cycle: estrogen effects in young women. Neuropsychologia. 2002; 40: 518-529. [87] Maki PM. Estrogen effects on the hippocampus and frontal lobes. Int. J. Fertil. Womens

[88] Markou A, Duka T, Prelevic GM. Estrogens and brain function. Hormones (Athens).

[89] Marquis S, Moore MM, Howieson DB et al. Independent predictors of cognitive

[90] McEwen B, Akama K, Alves S et al. Tracking the estrogen receptor in neurons: Implications for estrogen-induced synapse formation. PNAS. 2001; 13: 7093–7100. [91] McEwen, BS; Alves, SH. Estrogen actions in the central nervous system. Endocr Rev,

[92] McEwen, B; Akama, K; Alves, S; et al. Tracking the estrogen receptor in neurons: Implications for estrogen-induced synapse formation. PNAS, 2001; 13: 7093–7100. [93] McEwen B. Estrogen actions throughout the brain. Recent Prog. Horm. Res. 2002; 57:

[94] McEwen, BS. Stress, sex, and neural adaptation to a changing environment:

[97] Milner B. Interhemispheric differences in the localization of psychological processes in

[98] Milner TA, Ayoola K, Drake CT et al. Ultrastructural localization of estrogen receptor

[95] McGaugh JL. Memory – A Century of Consolidation. Science. 2000; 287: 248–251. [96] Micevych PE, Mermelstein PG. Membrane estrogen receptors acting through

the brain. Mol. Neurobiol. 2008; 38 (1): 66-77.

man. Br. Med. Bull. 1971; 27: 272–277.

mechanisms of neuronal remodeling. Ann N Y Acad Sci., 2010; 1204 Suppl E: 38-59.

metabotropic glutamate receptors: an emerging mechanism of estrogen action in

beta immunoreactivity in the rat hippocampal formation. J. Comp Neurol. 2005;

decline in healthy elderly persons. Arch. Neurol. 2002; 59: 601–606.

a D2 dopamine receptor agonist. J. Cogn. Neurosci. 1991; 4:58–68.

ovariectomized female rats. Endocrinology. 2005; 146:287–293.

Sci. USA. 2004; 101: 2185–2190.

Behav. 1998; 34: 149–162.

Med. 2005; 50: 67-71.

2007; 4: 9-17.

1999; 20:279–307.

357-384.

491:81-95.

11:334–343.

51: 181-182.

protein immunoreactivity and spatial memory in female mice. Proc. Natl. Acad.

hippocampal synaptic plasticity and improves memory. Nat. Neurosci. 2008;

spatial memory task and effects levels of monoaminergic neurotransmitters. Horm.

both induce rapid spine synapse formation in the CA1 hippocampal subfield of


[61] Henderson, V.W. Gonadal hormones and cognitive aging: a midlife perspective.

[62] Hruska Z, Dohanich GP. The effects of chronic estradiol treatment on working

[63] Jakob RL, Goldman-Rakic PS. 5-hydroxytryptamine2a serotonin receptors in the primate

pyramidal cell apical dendrites. Proc. Natl. Acad. Sci. USA. 1998; 95: 735–740. [64] Janowski JS, Chavez B, Orwoll E. Sex steroids modify working memory. J. Cogn.

[65] Jelks KB, Wylie R, Floyd CL, McAllister AK, Wise P. Estradiol targets synaptic proteins

[67] Jonides J, Smith EE, Koeppe RA, Awh E, Minoshima S, Mintun MA. Spatial working memory in humans as revealed by PET. Nature. 1993; 363: 623–625. [68] Kee KS, Kern RS, Marshall BD Jr, Green MF. Risperidone versus haloperidol for

[69] Korol DL. Role of estrogen in balancing contributions from multiple memory systems.

[70] Kritzer MF, Kohama SG. Ovarian hormones differentially influence immuno-reactivity

[71] Kritzer MF, Kohama SG. Ovarian hormones influence the morphology, distribution,

prefrontal cortex of adult rhesus monkeys. J. Comp. Neurol. 1998; 395 :1–17. [72] Lacreuse A, Wilson ME, Herndon JG. Estradiol, but not raloxifene, improves aspects of

[73] Lacreuse, A. Effects of ovarian hormones on cognitive function in nonhuman primates.

[74] Lacreuse J, Martin-Malivel HS, Herndon JG, Effects of the menstrual cycle on looking preferences for faces in female rhesus monkeys. Anim. Cogn. 2007; 105–115. [75] LeBlanc ES, Neiss MB, Carello PE, Samuels MH, Janowsky JS. Hot flashes and estrogen

[76] Ledoux VA, Woolley CS. Evidence that disinhibition is associated with a decrease in

[77] Lee SJ, McEwen BS. Neurotrophic and neuroprotective actions of estrogens and their therapeutic implications. Annu. Rev. Pharmacol. Toxicol. 2001; 41: 569–591.

critical role of estrogen receptor-alpha. J. Neurosci. 2007; 27: 6903-6913. [66] Joffe H, Hall JE, Gruber S et al. Estrogen therapy selectively enhances prefrontal

postmenopausal women. Menopause. 2006; 13: 411-422.

memory deficits induced by combined infusion of beta-amyloid (1-42) and ibotenic

cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in

to induce glutamatergic synapse formation in cultured hippocampal neurons:

cognitive processes: a randomized, double-blind, placebo-controlled study with functional magnetic resonance imaging in perimenopausal and recently

perception of emotion in treatment-resistant schizophrenia: preliminary findings.

for dopamine β-hydroxylase, choline acetyltransferase, and serotonin in the dorsolateral prefrontal cortex of adult rhesus monkeys. J. Comp. Neurol. 1999; 409:

and density of tyrosine hydroxylase immunoreactive axons in the dorsolateral

spatial working memory in aged ovariectomized rhesus monkeys. Neurobiol.

therapy do not influence cognition in early menopausal women. Menopause. 2007;

number of vesicles available for release at inhibitory synapses. J. Neurosci. 2005; 25:

Womens Health (Lond Engl), 2011; Jan 7(1): 81-93.

acid. Horm. Behav. 2007; 52 (3): 297-306.

Schizophr. Res. 1998; 31 (2-3): 159-65.

438–451.

14: 191-202.

971-976.

Aging. 2002; 23: 589–600.

Neuroscience, 2006; 138(3): 859-67.

Neurobiol. Learn. Mem. 2004; 82: 309–323.

Neurosci. 2000; 12: 407-414.


Estrogen Influences on Cognition 181

[119] Repovs G, Baddeley A. The multi-component model of working memory: explorations in experimental cognitive psychology. Neuroscience. 2006; 139: 5-21. [120] Resende MC, Tavares MCH, Tomaz C. Ontogenetic dissociation between habit

[121] Rhodes ME, Frye CA. ERbeta-selective SERMs produce mnemonic enhancing effects

[122] Rissman EF, Heck AL, Leonard JE, Shupnik MA, Gustafsson JA. Disruption of

[123] Roberts JA, Gilardi KV, Lasley B, Rapp PR. Reproductive senescence predicts cognitive decline in aged female monkeys. Neuroreport. 1997; 8: 2047–2051. [124] Rubinow MJ, Arseneau LM, Beverly JL, Juraska JM. Effect of the estrous cycle on

[125] Rudick CN, Woolley CS. Estrogen regulates functional inhibition of hippocampal CA1 pyramidal cells in the adult female rat. J. Neurosci. 2001; 21: 6532– 6543. [126] Rudick CN, Woolley CS. Selective estrogen receptor modulators regulate phasic

[127] Sandstrom NJ, Rowan MH. Acute pretreatment with estradiol protects against CA1

[128] Sandstrom NJ, Williams CL. Memory retention is modulated by acute estradiol and

[129] Sandstrom NJ, Williams CL. Spatial memory retention is enhanced by acute and

[130] Scharfman HE, Hintz TM, Gomez J et al. Changes in hippocampal function of

[131] Shaywitz SE, Shaywitz BA, Pugh KR et al. Effect of estrogen on brain activation

[132] Sherwin BB, Henry JF. Brain aging modulates the neuroprotective effects of estrogen

[133] Sherwin BB. Estrogen and cognitive function in women. Endocr. Rev. 2003; 24: 133–

[134] Sherwin BB. Estrogen effects on cognition in menopausal women. Neurology. 1997;

[135] Shughrue PJ, Merchenthaler I. Distribution of estrogen receptor β immunoreactivity in the rat central nervous system. J. Comp. Neurol. 2001; 436: 64–81. [136] Shughrue PJ, Merchenthaler I. Estrogen is more than just in ''sex hormones'': novel

progesterone replacement. Behav. Neurosci. 2001; 115: 384–393.

continuous estradiol replacement. Horm. Behav. 2004; 45: 128–135.

preovulatory estrogen surge. Eur. J. Neurosci. 2007; 26: 2595–2612.

Learn. Mem. 2003; 79: 19-24.

Sci. USA. 2002; 99: 3996–4001.

Horm. Behav. 2007; 51: 335–345.

Neuroendocrinol. 2008; 29: 88–113.

Neuroendocrinol. 2000; 21: 95-101.

2004; 118: 863–868.

144: 179–187.

281: 1197–1202.

151.

48: S21–S26.

183–191.

learning and recognition memory in capuchin monkeys (Cebus apella). Neurobiol.

in the inhibitory avoidance and water maze tasks. Neurobiol. Learn. Mem. 2006; 85:

estrogen receptor b gene impairs spatial learning in female mice. Proc. Natl. Acad.

water maze acquisition depends on the temperature of the water. Behav. Neurosci.

activation of hippocampal CA1 pyramidal cells by estrogen. Endocrinology. 2003;

cell loss and spatial learning impairments resulting from transient global ischemia.

ovariectomized rats after sequential low doses of estradiol to simulate the

patterns in postmenopausal women during working memory tasks. JAMA. 1999;

on selective aspects of cognition in women: A critical review. Front.

sites for estrogen action in the hippocampus and cerebral cortex. Front.



[99] Mitra SW, Hoskin E, Yudkovitz J et al. Immunolocalization of estrogen receptor beta in

[100] Mumby DG, Gaskin S, Glenn MJ, Schramek TE, Lehmann H. Hippocampal damage

[101] Northoff G, Richter A, Gessner M et al. Functional dissociation between medial and

emotions: a combined fMRI/MEG study. Cereb. Cortex. 2000; 10 (1): 93-107. [102] O'Neal M, Means L, Poole M, Hamm R. Estrogen affects performance of

[103] Osterlund MK, Hurd YL. Estrogen receptors in the human forebrain and the relation

[104] Owen AM, Doyon J, Petrides M, Evans AC. Planning and spatial working memory:

[105] Owen AM, Sahakian BJ, Semple J, Polkey CE, Robbins TW. Visuo-spatial short-term

or amygdalo-hippocampectomy in man. Neuropsychologia. 1995; 33: 1–24. [106] Petrides M, Alivisatos B, Evans AC, Meyer E. Dissociation of human mid-

[107] Petrides M, Alivisatos B, Meyer E. Functional activation of the human frontal cortex

[108] Petrides M. Impairments on nonspatial self-ordered and externally ordered working

[109] Pettersson K, Gustafsson JA. Role of estrogen receptor beta in estrogen action. Annu.

[113] Postle BR, Berger JS, D'Esposito M. Functional neuroanatomical double dissociation

[114] Prange-Kiel J, Rune GM Direct and indirect effects of estrogen on rat hippocampus.

performance. Proc. Natl. Acad. Sci USA. 1999; 96: 12959–12964.

[115] Preuschoft S. Primate faces and facial expressions. Soc. Res. 2000; 67: 245-271. [116] Rabbitt P, Lowe C. Patterns of cognitive aging. Psychol. Res. 2000; 63: 308–316. [117] Rapp PR, Morrison JH, Roberts JA. Cyclic estrogen replacement improves cognitive function in aged ovariectomized rhesus monkeys. J. Neurosci. 2003; 23: 5708–5714. [118] Rehman HU, Masson EA. Neuroendocrinology of Female Aging. Gend. Med. 2005; 1:

[110] Pfaff DW. Estrogen and Brain Function. Springer-Verlag (Ed.), New York. 1980. [111] Pike C, Estrogen modulates neuronal Bcl-xL expression and beta-amyloid-induced apoptosis: relevance to Alzheimer's disease. J. Neurochem. 1999; 72: 1552–1563. [112] Pompili A, Tomaz C, Arnone B, Tavares MC, Gasbarri A. Working and reference

to neuropsychiatric disorders. Prog. Neurobiol. 2001; 64: 251–267.

144: 2055-2067.

364.

Learn. Mem. 2002; 9: 49–57.

Psychoneuroendocrinology. 1996; 21: 51–65.

Natl. Acad. Sci. USA. 1993; 90: 873–877.

monkey. J. Neurosci. 1995; 15: 359–375.

females. Behav. Brain Res. 2010; 213: 10-18."

Rev. Physiol. 2001; 63:165-192.

Neuroscience. 2006; 138: 765-772.

41-56.

USA. 1993; 90: 878–882.

the mouse brain: comparison with estrogen receptor alpha. Endocrinology. 2003;

and exploratory preferences in rats: memory for objects, places, and contexts.

lateral prefrontal cortical spatiotemporal activation in negative and positive

ovariectomized rats in a two-choice water escape working memory task.

A positron emission tomography study in humans. Eur. J. Neurosci. 1996; 8: 353–

recognition memory and learning after temporal lobe excisions, frontal lobe excisions

dorsolateral from posterior dorsolateral frontal cortex in memory processing. Proc.

during the performance of verbal working memory tasks. Proc. Natl. Acad. Aci.

memory tasks after lesions of the mid-dorsal part of the lateral frontal cortex in the

memory across the estrous cycle of rat: a long term study in gonadally intact

of mnemonic and executive control processes contributing to working memory


**9** 

*USA* 

**An Integrative Review of** 

Victoria Luine1 and Maya Frankfurt2

**Estradiol Effects on Dendritic** 

**Spines and Memory over the Lifespan** 

Estradiol enhances some aspects of learning and memory in both humans and animal models. These enhancements are present throughout the adult lifespan (Luine, 2008) and extend into old age (Frick, 2008). While many neurochemicals and neurotrophins have been shown to be regulated by estrogen, the mechanism(s) responsible for estrogen's positive effects on cognition remain elusive. It has, however, been demonstrated that gonadal hormones, both estrogens and progestins, influence neural morphology in areas important for cognitive function such as the hippocampus and medial prefrontal cortex (PFC). Spines, which are located on the dendrites of pyramidal neurons in both of these areas, have been shown to contribute to cognitive function (Morgado-Bernal, 2011). Therefore, we will review estradiol's effects on dendritic spine density in the hippocampus and PFC in relation to cognitive function. Moreover, we also consider whether changes in spine density are important for estrogen's role in the maintenance of memory. The studies are primarily from our own laboratories, but, when available, data from other labs are compared. In our studies, spine density has been investigated by Golgi impregnation, and memory has been evaluated using the spatial memory tasks of radial arm maze and object placement, and non-spatial memory has been assessed by object recognition. In most of the studies to be discussed, both morphology and cognitive function were assessed in the subjects. This current research provides substantial data suggesting a relationship between hormones, spines and cognitive function, but we point out the need for further research to establish causal relationships between these variables and to identify how spines promote memory

Neuron to neuron communication occurs mainly when axons synapse on dendrites. Dendritic spines are small protrusions of the dendrite which receive the majority of synaptic input. Although dendritic spines are present on many neurons, they are extremely numerous on pyramidal cells of both the hippocampus and the PFC (See Figure 1, schematic

consolidation and are integrated into memory networks.

**2. Dendritic spines and memory** 

**1. Introduction** 

*1Department of Psychology, Hunter College of CUNY, New York, 2Department of Science Education, Hofstra North Shore-LIJ School of Medicine, 500 Hofstra University, Hempstead,* 

