| Mice |
| Agís-Balboa et al., 2007 |
Swiss-Webster |
Adulte
|
4 weeks |
Male |
Group housed male mice |
Expression of 5α-reductase Type I (5α-RI) and 3α-hydroxysteroid dehydrogenase (3α-HSD) mRNA in different brain regions |
In socially isolated mice, the expression of 5α-RI mRNA is down-regulated in the frontal (prelimbic and infralimbic) cortex, hippocampus, and amygdala but not in the striatum compared with group housed mice. Expression of 3α-HSD mRNA fails to change. Socially isolated mice show a 37% decrease in the intensity of the 5α-RI in situ hybridization signal in frontal cortex layer V/VI pyramidal neurons. However, this signal fails to change in layers II/III pyramidal neurons. After protracted social isolation, the intensity of the 5α-RI mRNA in situ hybridization signal is decreased by 75% in CA3 glutamatergic pyramidal neurons; by 68% in dentate gyrus (DG) glutamatergic granule cells; and by 44% in glutamatergic neurons of the basolateral amygdala. No effect of social isolation on 5α-RI or 3α-HSD mRNA signal intensity in thalamus. Neuronal count is similar in isolates and group housed in the hippocampus CA3 layer, dentate gyrus, and basolateral amygdala.
|
| Berry et al., 2012 |
C57BL/6J strain |
Adult |
21 days |
12 male |
Group housed male mice (n = 16) + group housed male mice submitted to stressf (n = 16) |
Ratio of adrenal weight to body weight; brain-derived neurotrophic factor (BDNF) levels measured in the hypothalamus, hippocampus, frontal cortex, striatum, & midbrain on 8 subjects per group randomly chosen from pool of subjects |
Despite no difference in body weight between groups, socially isolated mice showed the highest values for adrenals/body weight ratio. Socially isolated mice had lower levels of neurotrophin BDNF compared to social group for frontal cortex and hippocampus and compared to social group and social stress group for hypothalamus and midbrain. Socially isolated mice also showed a tendency to reduced BDNF levels in the striatum when compared to social group subjects.
|
| Liu et al., 2012 |
C57Bl/6J strain |
Adult |
2–8 weeks |
6 male, 9 female |
Group housed male mice (n = 5) & female mice (n = 12) |
Myelination changes |
Decreased myelin gene transcripts can be observed in regions that are functionally relevant to the control of social behavior, such as prefrontal cortex, but not in corpus callosum or nucleus accumbens of socially isolated mice. 2 weeks are enough to induce decrease of myelination thickness.
|
| Pinna et al., 2003 |
Swiss-Webster |
Adult |
1 day–8 weeks |
Male & female |
Group housed mice (n = 5–6) |
5α-reductase Type I mRNA |
|
| Rats |
| Barrientos et al., 2003 |
Sprague-Dawley |
Adultg
|
6 hr |
2–6 male |
2 male rats housed together with 2 other rats (Experiment 1) |
BDNF mRNA expression |
Social isolation immediately after contextual fear conditioning reduces BDNF mRNA in the dentate gyrus and the CA3 region of the hippocampus. No effect of social isolation on BDNF mRNA in the parietal cortex. Effect of social isolation on hippocampal BDNF mRNA can be blocked by intra-hippocampal interleukin (IL)-1 receptor antagonist, when administered prior to the social isolation period.
|
| Barrot et al., 2005 |
Sprague-Dawley |
7–8 weeks of age |
10–14 weeks |
6 male |
7 male rats housed together (2 per cage) |
cAMP response element (CRE) binding protein (CREB) activity |
Social isolation decreases CREB activity by 34% in the shell of the nucleus accumbens (NAcSh) after 10–12 weeks. This local reduction in CREB activity mediates the isolation-induced increases in anxious behavior.
|
| Bhide & Bedi, 1984 |
Lister hooded |
85 days of age |
30 days |
12 rats |
12 rats group housed in a large metal cage with 6–10 toysf
|
Cortical depth, nuclear diameter, and numerical density of neurons and glial cells; perikaryal size and volume; forebrain weight and size |
Socially isolated rats have a lighter forebrain than controls. Socially isolated rats have a shorter forebrain lengths than controls. No significant differences in cortical depth between the isolated and controls, except in one brain section of the left occipital cortex (area 17) where the superior colliculus is clearly defined and the hippocampus is continuous as it extends ventrally. No other significant differences between isolates and controls, except a significant effect of environment on neuron/glial cell ratio.
|
| Bjørnebekk et al., 2007 |
Flinders sensitive line & Sprague-Dawley |
29–30 weeks of age |
7 weeks |
8 Flinders sensitive line females and 8 Sprague-Dawley females |
8 Flinders sensitive line females group housed together (4 per cage)
8 Sprague-Dawley females group housed together (4 per cage) |
Survival of proliferating cells in the dentate gyrus of the hippocampus, as measured with BrdU labeled cells, brain-derived neurotrophic factor (BDNF), neuropeptide Y (NPY), and serotonin 5HT2A receptor mRNA |
Social isolation differentially affects BrdU-labeled cells in the two strains. While the number of BrdU labeled cells is markedly increased in socially isolated Flinders sensitive line rats, no change is observed in Sprague-Dawley rats. mRNAs encoding BDNF reveals differences between the two strains; however, the difference is restricted to group housed rats. Social isolation selectively decreases mRNA levels in the Sprague-Dawley strain, which tends to diminish the differences between the two strains. NPY mRNA levels are lower in Flinders sensitive line compared with Sprague-Dawley rats in both controls and socially isolated animals in the CA1 and CA3. Socially isolated Sprague-Dawley rats (but not isolated Flinders sensitive line) show decreased NPY mRNA levels in all analyzed subregions. Housing does not affect 5HT2A receptor mRNA levels within the strains.
|
| Diamond et al., 1972 |
S1 strain |
60 and 105 days of age |
30–80 days |
25 60-day-old male and 18 105-day-old male |
A group of 25 60-day-old male rats and 18 105-day-old male rats group housed together (10–12 rats per cage) |
Cortical depth in frontal, somesthetic, and occipital cortex |
In the 60-day-old group, 30 days of social isolation induces significant cortical depth differences (compared to controls) in every segment of the occipital cortex. In the 60-day-old group, the effect of 30 days of social isolation is greater in the occipital cortex than in the somesthetic cortex. In the 80-day experiments with the older animals, 105-day-old rats, the cortical depth changes are not as marked as in the 30-day experiments with younger (60-day-old) rats.
|
| Diamond et al., 1975 |
S1 strain |
60 and 105 days of age |
30–80 days |
19 60-day-old male and 18 105-day-old male |
19 60-day-old male rats and 18 105-day-old male rats group housed together (10–12 rats per cage for each age range) with access to toysf
|
Cortical neuronal nuclei and perikarya dimensions |
Neither of the two age ranges show any neuronal nuclei differences between isolates or controls. In the 60-day-old group, 30 days of social isolation induces smaller (by 4.5%) perikarya than controls.
|
| Diamond et al., 1976 |
Rats |
60 and 105 days of age |
1, 4, or 30 days for the 60-day-old rats; 80 days for the 105-day-old rats |
A total of 266 rats |
60- and 105-day-old rats (total n = 266f) group housed together per age range |
Cortical depth in motor, somesthetic, and occipital cortex |
In the 60-day-old group, 1 day of social isolation does not induce any cortical differences with controls. In the 60-day-old group, 4 days of social isolation significantly reduces cortical differences in the medial and dorsal (but not in the lateral) visual cortex, compared to controls. In the 60-day-old group, 30 days of social isolation significantly reduces cortical differences in entire visual cortex and the somesthetic cortex (but not the motor cortex) compared to controls. In the 105-day-old group, 80 days of social isolation only reduces cortical depth in the medial part of the visual cortex, compared to controls.
|
| Djordjevic et al., 2010 |
Wistar |
3 months of age |
21 days |
Male |
A group of unstressed animals (control group) + a group of rats exposed to an acute stress (i.e., 30-min immobilization period) + a group exposed to a combined stress (i.e., a 21-day social isolation period followed by a 30-min immobilization period)
In each comparison group, rats were housed 4 per cage |
Glucocorticoid receptor (GR) and nuclear factor kappa B (NFkB) protein and mRNA expression, and DNA defragmentation in the prefrontal cortex (PFC) |
The GR gene expression in the PFC is down-regulated only after chronic stress (i.e., here, a 21-day period of social isolation). NFkB protein levels are decreased in the nucleus under acute and combined stress and increased in the cytoplasm after social isolation. NFkB mRNA level remains unchanged under all three types of stress. Both social isolation and social isolation + stress result in an increase in DNA fragmentation (fragments seen after DNA cleavage associated with apoptosis) in the PFC.
|
| Garrido et al., 2013 |
Wistar |
3 months of age |
12 weeks |
Male |
A group of male rats housed together (10–12 animals per cage) with 2 running wheels, tunnels, and different objectsf
|
Corticosterone, dopamine, and acetylcholine responses to acute restraint stress in the PFC of the awake rat and the mRNA levels of GRs in the PFC |
Socially isolated animals showed higher increases of corticosterone and dopamine but not of acetylcholine than group housed animals in the PFC in response to acute restraint stress (20 min). In the PFC, GR mRNA levels showed a trend toward an enhancement in group housed animals.
|
| A. K. Mohammed et al., 1990 |
Sprague-Dawley |
52 days of age |
30 days |
12 male (6 of which were submitted to 1 day of automatic activity cages + 3 days in the Morris water maze after social isolation) |
12 male group housed together (6 per cage) + 12 other male group housed together (3 per cage). Half of the animals of each group were submitted to 1 day of automatic activity cages + 3 days in the Morris water maze after social isolation |
Nerve growth factor (NGF) content in the cortex, hippocampus, and septum |
No significant differences of NGF levels between groups after 30 days of social isolation. When followed by 4 days of physical exercises, a 30-day social isolation induces higher levels of NGF in the septum and hippocampus (compared to a 6-per-cage group). Socially isolated rats show a 30% increase of the NGF level following behavioral tests.
|
| Moser et al., 1997 |
Rats |
Adultg
|
14–18 days |
4–5 male |
10–11 male rats spatially trained together in a complex environment 4 hr per day and then housed in pairs + 6–7 nontrained pair housed male rats |
Spine density on a sample of oblique secondary branches of apical dendrites of CA1 pyramidal cells of the hippocampus; distribution of new spines on basal dendrites |
The mean spine density for the apical dendrites in the different groups does not differ significantly. In contrast to the apical dendrites, there is an increased spine density on CA1 basal dendrites following spatial training when compared with paired and isolated animals. Analysis of the spine density plots shows that the enhanced spine density after spatial training is found in most cells recorded from the trained group. The trained group has a significant right-skewed tail of the spine distribution, that is, training causes high spine density to occur in a small subset of dendritic segments. The isolated group has a significant left-skewed spine distribution, indicating that some of the dendritic segments are undersupplied with spines, whereas the paired group displays no asymmetry.
|
| Nilsson et al., 1999 |
Sprague-Dawley |
9 weeks of age |
4 weeks |
10 female |
12 female group housed (6 per cage) with toysf
|
Proliferating cells in the dentate gyrus of the hippocampus, as measured with BrdU labeled cells |
Socially isolated rats show less BrdU cells than controls in the granule cell layer of the dentate gyrus. No differences between controls and socially isolated animals in the number of BrdU-positive cells in the hilar region of the dentate gyrus.
|
| Pham et al., 1999 |
Sprague-Dawley |
2 months of ageg
|
1 year |
15 male |
16 male rats housed together (8 per cage) with toysf
|
Nerve growth factor (NGF) levels in hippocampus, visual cortex, entorhinal cortex, and hypothalamus |
Socially isolated rats (n = 7) show lower NGF in the hippocampus, visual cortex and entorhinal cortex, compared with controls (n = 8). No significant difference was observed in the hypothalamus between isolates (n = 7) and controls (n = 8).
|
| Rosenzweig et al., 1968 |
S3 strain (Experiments I–IV); S1 strain (Experiment V) |
60 days of age |
55 days (Experiment I)
56 days (Experiment II)
54 days (Experiment III)
31 days (Experiment IV)
30 days (Experiment V) |
10 male (Experiments I & III)
11 male (Experiment II & IV) |
10–11 male rats group housed together for 24 hr with toys (24 hr enriched condition) + 10–11 male rats group housed together for 4.5 hr with toys + 10–11 male rats group housed together for 2.5 hr with toysf (Experiments I–II)
A group of male rats (n = 10) housed together with toysf for 2 hr, while the other 22 hr of the day were spent in 3-per-cage group housing (Experiment III)
A group of male rats (n = 11) housed together (5–6 per cage) for 2 hr after receiving saline injection, with access to toys for 90 min, while the other 22 hr of the day were spent in social isolation (Experiments IV and V) |
Brain weight and brain chemistry of acetylcholinesterase (AChE) and cholinesterase (ChE) |
Socially isolated rats (n = 21) have lighter brain tissue (than controls) in the occipital cortex and motor cortex (Experiment I and II). No significant difference in brain tissue weight between isolates and controls in the somesthetic cortex (Experiment I and II). Socially isolated rats show more AChE activity in the occipital cortex than the 2.5 hr socially enriched group (Experiments I and II) or than the 2 hr socially enriched group (Experiment V). Socially isolated rats show higher AchE activity in the cortex and lower in the rest of the brain than the 2 hr socially enriched group (Experiments III–V). No differences in ChE between groups in any brain regions. Even though 22 hr per day were spent in isolation by both groups (Experiment IV), 2 hr/day of socially enriched experience for 31 days produce a significant increase in brain weight from the socially isolated rats.
|
| Scaccianoce et al., 2006 |
Sprague-Dawley |
2 months of age |
8 weeks |
8 male |
8 pair housed male rats |
Brain-derived neurotrophic factor (BDNF) expression in the hippocampus, striatum, and prefrontal cortex |
|
| Spritzer et al., 2011 |
Sprague-Dawley |
55 days old |
34 days |
8 male after a sham surgery; 8 male rats after castration (Experiment 1); 8 castrated male receiving daily testosterone injection; 8 castrated male receiving daily sesame oil injections |
8 male rats pair housed after a sham surgery; 8 male rats pair housed after castration (Experiment 1); 8 castrated male pair housed with daily testosterone injection; 8 castrated male pair housed with daily sesame oil injection (Experiment 2) |
Number of BrdU labeled cells in the granule cell layer and subgranular zone of the dentate gyrus; volume of brain regions; serum testosterone levels |
Experiment 1
Castrated rats have significantly fewer BrdU-labeled cells in the granule cell layer and subgranular zone than the sham-castrated rats. No significant main effect of housing or Housing × Condition interaction for number of BrdU-labeled cells in the granule cell layer and subgranular zone of the dentate gyrus. Planned contrasts reveal that the castrate/isolated group have significantly fewer BrdU-labeled cells in the granule cell layer and subgranular zone than either the sham/pair-housed group or the sham/isolated group, but only a trend toward significance is noted for the difference between the castrate/isolated group and the castrate/pair-housed group. Socially isolated rats have significantly fewer BrdU-labeled cells in the hilus than pair housed rats. -
No significant main effect of housing or Housing × Condition interaction for number of BrdU-labeled cells in hilus.
Experiment 2
Socially isolated rats have significantly fewer BrdU-labeled cells in the granule cell layer and subgranular zone than pair-housed rats. Testosterone-injected rats tend to have fewer BrdU-labeled cells in the dentate gyrus than did oil-injected controls. The Housing × Condition interaction is not significant.
|
| Stranahan et al., 2006 |
Sprague-Dawley |
Adult |
12 days |
6 male |
Group housed male rats (3 per cage)f with or without running activity |
Number of BrdU labeled cells in the dentate gyrus |
Runners housed in groups exhibit a significant increase in the number of BrdU labeled cells in the dentate gyrus, compared to group-housed controls. Individually-housed runners show the opposite effect, that is, a significant decrease in the number of BrdU labeled cells, compared to individually-housed controls. No significant differences in BrdU labeled cell number were seen between group- and individually-housed controls.
|
| Wallace et al., 2009 |
Sprague-Dawley |
7–8 weeks |
10–12 weeks |
Male |
Pair housed |
cAMP response element (CRE) binding protein (CREB) activity in the shell of the nucleus accumbens (NAcSh) |
Increased anxiety and depressive behavior as well as reduced CREB activity in the NAcSh in the socially isolated, relative to pair-housed, animals. Chronic administration of imipramine, a tricyclic antidepressant, normalize CREB activity in the NAcSh and reverse the anxiety-like and depressive-like behaviors in the socially isolated rats. The analysis of DNA expression arrays suggests that social isolation reduces CREB activity in the NAcSh, which serves to upregulate several K+ channels and depresses the excitability of NAcSh neurons, leading to anxiety-like behaviors.
|
| Westenbroek et al., 2004 |
Wistar |
3 weeks |
3 months of age |
10 male and 10 female |
14 male and 14 female were housed in unisex groups of four rats |
Survival of proliferating cells in the dentate gyrus of the hippocampus |
Social isolation, especially when combined with chronic stress, induces a decrease in BrdU-labeling in males, whereas it induces an increase BrdU-labeling in females.
|
| Voles |
| Fowler et al. 2002 |
Prairie voles (Microtus ochrogaster) |
85–135 days of ageh
|
2 days or 3 weeks |
7 female for the 2-day social isolation condition; 7 female for the 3-week social isolation condition (Experiment 1); 5 female for the 2-day social isolation condition (Experiment 2) |
Housed with an unfamiliar male (n = 7 for the 2-day condition; n = 6 for the 3-week condition, Experiment 1; n = 6, Experiment 2; male exposure groups); housed with an unfamiliar female (n = 6 for the 2-day condition; n = 8 for the 3-week condition, Experiment 1; n = 6, Experiment 2; female exposure groups) |
Number of proliferating BrdU-labeled cells (Experiment 1) and apoptosis rate and DNA fragmentation (Experiment 2) in the subventricular zone and dentate gyrus of the hippocampus |
Social isolation decreases the number of BrdU-labeled cells in the amygdala and hypothalamus compared with 2 days of male exposure. Three weeks later, group differences in BrdU labeling generally persist in the amygdala, whereas in the hypothalamus, the male-exposed animals have more BrdU-labeled cells than do the female-exposed animals. In the subventricular zone, 2 days of social isolation increases the number of BrdU-labeled cells compared to female exposure, but this difference vanishes 3 weeks later. Group differences in the number of cells undergoing apoptosis are subtle and do not seem to account for the observed differences in BrdU labeling.
|
| Grippo, Cushing, & Carter, 2007 |
Prairie voles (Microtus ochrogaster) |
60–120 days of age |
60 days |
10 female |
10 pair housed female |
Numbers of corticotropin-releasing factor-and oxytocin-immunoreactive cells in the paraventricular nucleus of the hypothalamus, and circulating levels of hormones and peptide in response to an acute social stressor (resident–intruder test). |
Chronic social isolation produces anhedonia, measured by a reduction in sucrose intake and sucrose preference relative to paired animals. Compared to paired animals, socially isolated prairie voles display increased plasma hormone and peptide levels (oxytocin, arginine vasopressin, and corticosterone) following a 5-min resident–intruder test, mirrored by an increased number of oxytocin- and corticotropin-releasing factor-immunoreactive cells in the hypothalamic paraventricular nucleus.
|
| Grippo Gerena, & Huang, 2007 |
Prairie voles (Microtus ochrogaster) |
60–90 days of age |
4 weeks |
8 female and 8 male |
8 female and 8 male pair housed with a same-sex sibling |
Basal central (in hypothalamic paraventricular nucleus, PVN), and plasma circulating hormones and peptides; c-Fos expression in PVN |
Oxytocin-immunoreactive cell density is higher in the PVN and plasma oxytocin is elevated in socially isolated females, but not males (Experiment 1). Compared to paired animals, plasma oxytocin, adrenocorticotropic hormone (ACTH) and corticosterone are elevated in socially isolated females (Experiment 2). The proportion of cells double-labeled for c-Fos and oxytocin or c-Fos and corticotropin releasing factor (CRF) is elevated in socially isolated females. In males, the proportion of cells double-labeled for c-Fos and oxytocin is elevated following a resident–intruder test (Experiment 2).
|
| Lieberwirth et al., 2012 |
Prairie voles (Microtus ochrogaster) |
90–120 days of age |
14 days |
8–9 female |
8–9 female pair housed with a same-sex vole |
Cell proliferation and survival, neuronal differentiation, and cell death in subregions of the amygdala and hippocampus |
Social isolation reduces cell proliferation, survival, and neuronal differentiation and alters cell death in the dentate gyrus of the hippocampus and the amygdala. No effect of social isolation in the medial preoptic area. Social isolation reduces cell proliferation in the medial preoptic area and cell survival in the ventromedial hypothalamus.
|
| Pournajafi-Nazarloo & Partoo, 2011 |
Prairie voles (Microtus ochrogaster) |
2 months of age |
1 hr total (single social isolation) or 1 hr every day for 4 weeks (repeated social isolation) or 4 continuous weeks (chronic social isolation) |
8 per group |
Animals were subjected to single, repeated, or chronic social isolation |
Corticotropin-releasing hormone (CRH) receptor (CRH-R1 mRNA) and Type 2 CRH receptor (CRH-R2 mRNA) expression in the hypothalamus, hippocampus, and pituitary gland |
Single or repeated isolation increases hypothalamic CRH mRNA expression. No changes in CRH-R1 mRNA in the hypothalamus. Continuous social isolation shows no effect on hypothalamic CRH or CRH-R1 mRNAs in female or male animals. However, continuous social isolation reduces hypothalamic CRH-R2 mRNA. Single or repeated isolation, but not chronic social isolation, significantly increases CRH-R1 mRNA and decreases CRH-R2 mRNA in the pituitary. Despite elevated CRH mRNA expression, CRH-R1 and CRH-R2 mRNAs are not modulated in the hippocampus following single or repeated isolation. Chronic social isolation increases CRH-R2 mRNA expression in females and males, although it does not affect hippocampal CRH or CRHR1 mRNAs.
|
