M.A. Hofman, G.J. Boer, A.J.G.D. Holtmaat, E.J.W. Van Someren, J. Verhaagen and D.F. Swaab (Eds.) Progress in Brain Research, Vol. 138 0 2002 Elsevier Science B.V. All rights reserved CHAF’TER 8 Environmental enrichment and the brain ’ A .H . Mohammed ‘v*, SW. Zhu ‘, S. Darmopil I, J. Hjerling-Leffler 2, I?.Ernfors 2, B. Winblad I, M.C. Diamond 3, P.S. Eriksson 4 and N. Bogdanovic ’ ’ Division of Geriatric Medicine, NEUROTEC, Karolinska Institute& S-141 86 Huddinge, Sweden 2 Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-I 71 77 Stockholm, Sweden 3 Department of Integrative Biology, University of California, Berkeley, CA 94720-3140, USA 4 Deparmtent of Clinical Neuroscience, Sahlgrensko University Hospital, Giiteborg Universi& S-413 45 Gateborg, Sweden IntroductioIl animals can display differential brain architecture as a result of environmental influences is that of the An intriguing feature of the adult brain is its capacity blind cave dwelling fish Amblyopsis spelaea and its for structural and functional modification in response relative Chologaster agassizi. The former lives in to external stimuli. This plasticity of the adult ner- dark caves while the latter lives above ground in vous system has been the focus of research efforts swamps and streams. Comparison of the brains of for decades. The historical antecedents of ideas about these two related species of fish revealed that the brain changes in relation to experiential factors can ground dwelling A. spelae had degenerate eyes and been traced back to ancient Greece (Rosenzweig, a smaller optic tectum. Since the species uses smell 1996; Diamond, 2001) and has captured the imagi- more than vision, the olfactory tract and related te- nation of scientists, philosophers and writers. It was lencephalon were enlarged, as was the cerebellum. in the 18th century when it was hypothesised that By contrast, the C. agassizi living near the watersur- nervous tissue can respond to exercise by physi- face in daylight had a large tectum and well-formed cal growth. The impact of the environment on the eyes (Poulson, 1963). That evolutionary pressures brain was alluded by Charles Darwin (1874) in his can orchestrate such structural changes in the brains description of wild rabbits having increased brain of related species is self-evident. This can further size compared to domesticated rabbits. Nature is re- be exemplified by observations of measurable dif- pleted with examples of how wild animals like sheep, ferences in brains of, for example, domesticated ducks, and pigs differ in brain measures compared and wild rats (Kruska, 1975), turkeys (Ebinger and to their domesticated relatives. A dramatic illustra- Riihrs, 1995), pigs (Plogmann and Kruska, 1990) tion of nature’s experiment on how some species of and silver foxes (Popova et al., 1991). What was not expected is that in the labora- tory rats relatively minor variations in housing en- * Correspondence to: A.H. Mohammed, Division of Geri- vironment at adulthood could induce chemical and atric Medicine, NEUROTEC, Karolinska Institutet, S-141 86 Huddinge, Stockholm, Sweden. anatomical changes in the brain, as Bennett and E-mail: [email protected] colleagues demonstrated in the early 1960s. These 1 This paper is dedicated to Dr. Edward L. Bennett, Uni- studies, influenced by the initial speculations and versity of California, Berkeley, on the occasion of his 80th observations of Hebb (1949), were discordant with birthday. the then prevailing view that at adulthood the brain 110 is fixed and static and therefore not susceptible to Berkeley group and several other groups. It also ap- modification by environmental influences. The in- peared that the differences in brain weight could not vestigators found that housing adult rats in an en- be attributed to differences in body weight as the vironment rich in sensory stimuli induces measur- EC animals, which had higher brain weights, had able changes in gross brain structure and levels of lower body weights than the IC animals. The largest the enzyme acetylcholinesterase (Krech et al., 1960; EC-IC difference was found with respect to the oc- Bennett et al., 1964a,b; Diamond et al., 1964, 1966; cipital cortex (9.4%), and this led these investigators Rosenzweig and Bennett, 1969). This was followed and others to a systematic examination of various by demonstrations of environmentally induced neu- measures in the occipital cortex induced by EC. In roanatomical changes of finer structures, such as the different layers of the visual cortex analyses were dendritic branching, dendritic length and dendritic made of environmentally induced changes in neu- spine density (Globus et al., 1973; Diamond et al., ronal soma size, neuronal density, length of dendritic 1976). These seminal observations stimulated much branches, dendritic spine density, length of synapses research on the influence of enriched environment on and glial cell counts. In layer I, no differences were different aspects of brain function and behaviour. As found, while in the deeper layers consistent differ- a result, a voluminous literature from the last four ences between EC and IC rats were observed. It decades exists. Recent discoveries concerning envi- was found that rats from the enriched environment ronmentally induced increase in adult neurogenesis developed significantly thicker and longer cerebral (Van Praag et al., 2000) have given this paradigm a cortices compared to littermates from the impov- new resonance, resulting in a further increase in re- erished and standard environments (Bennett et al., ports. In this review, we will survey some of the work 1964a,b, 1970; Diamond et al., 1964, 1966, 1967, on the influence of enriched environment on the adult 1972; Altman et al., 1968; Walsh et al., 1971, 1973). brain, and provide new unpublished findings. EC animals had more glial cells, increased size of neuronal perikarya and nuclei in the cortex (Altman Effects on the cortex and Das, 1964; Diamond et al., 1966, 1967, 1975). These changes were largely seen in the occipital cor- In the enriched environment condition (EC) devised tex. Dendritic branching in occipital layer II stellate by Bennett et al., lo-12 rats are placed in large neurones was increased in EC animals (Holloway, cages (76 x 76 x 46 cm) containing some stimulus 1966). Further work showed that in pyramidal neu- objects such as balls, running wheels, tunnels, and rones and stellate neurones of the occipital cortex EC ladders (Bennett et al., 1964a, 1974; Rosenzweig and rats had more higher order dendritic branches than Bennett, 1969, 1996; Diamond, 1988). The ‘toys’ are their IC littermates. Differences in dendritic branch- changed daily. In contrast to this environmental com- ing patterns in the visual cortex were also observed plexity the impoverished environment condition (IC) predominantly in the basal dendrites (Greenough consisted of housing the animals singly in small and Volkmar, 1973). Changes in number of dendritic cages. In between these two environmental condi- spines were induced as a result of environmental tions a standard environment (SC) is employed and enrichment (Globus et al., 1973), and similarly the consists of housing three or four rats in laboratory differences were larger in the basal dendrites. In cor- group cages. Variations of environmental enrichment tical layers II and III the basal dendrites in pyramidal housing exists and have been used in different labo- neurones of EC animals showed an increase in length ratories. of terminal segments of the dendrites and increased In the initial studies, it was observed that differ- branching (Uylings et al., 1978). The alterations in ential housing of rats from 25 to 55 days of age re- dendritic branches and spines suggested changes in sulted in different brain weights between litter-mates individual synapses. Studies on dimensions of the housed in EC and IC environments (Rosenzweig et synapses revealed that in layer III and layer IV, EC al., 1962; Bennett et al., 1969; see also reviews by animals had longer post-synaptic thickening than IC Bennett, 1976, Bennett and Rosenzweig, 1970, and rats (Mollgaard et al., 1971; West and Greenough, Diamond, 1988). This finding was replicated by the 1972; Diamond et al., 1975). The neuroanatomical 111 changes in the visual cortex could at least in part be Recent studies have generated convincing evi- mediated by neurotrophins, as their levels increased dence of environmentally induced changes in the in the visual cortex of EC rats (Torasdotter et al., hippocampus of EC rats as compared to IC rats, in 1996, 1998), and the nerve growth factor inducible a wide array of biological variables. These studies (NGF-IA) immediate early gene, which is also in- have shown that EC induces hippocampal changes duced in EC animals’ visual cortex (Wallace et al., in gene expression and/or protein levels of neuro- 1995). Changes in mRNA levels in the brains of EC trophins (Falkenberg et al., 1992; Mohammed et al., animals were demonstrated in earlier studies (Fer- 1993; Torasdotter et al., 1996, 1998), glucocorti- chmin et al., 1970; Bennett, 1976; Ferchmin and coid receptors (Mohammed et al., 1993; Olsson et Eterovic, 1986). al., 1994), the Alzheimer amyloid precursor protein These neuroanatomical changes are likely to have (Huber et al., 1997), immediate early genes (Mo- functional consequences. Speculations that plastic hammed et al., 1993; Olsson et al., 1994), serotonin changes occurring at synaptic sites could be re- receptors (Rasmuson et al., 1998), AMPA receptor lated to long-term memory have been entertained by binding (Gag& et al., 1998) as well as in neuroge- some investigators at different times - from Tanzi nesis (York et al., 1989; Kempermann et al., 1997, and Cajal to Hebb and Kandel (for reviews see, 1998a,b; Nilsson et al., 1999). Exposure to a com- e.g. Rosenzweig, 1996; Diamond, 2001). Increased plex environment induces increased spine densities synaptic density and larger synaptic sites appear to in the hippocampal CA1 pyramidal cells (Moser et be associated with enhanced capacity for learning, al., 1994).