Smeyne Research

We are a social species; thus, it should not be surprising that the absence of social contact among those who are effectively isolated often has toxic physiological and psychological consequences. Isolation has many faces, that range from the unintended such as that which occurs as an unintended consequence of ageing and sickness (including living in a nursing home or an assisted living facility or even the isolation seen in the population of non-medical professionals who serve as caregivers) to that which is forced upon the individual (incarceration in solitary confinement). In fact, social isolation is a potent -but little understood- risk factor for morbidity and mortality, and its negative consequences are most profound among the elderly, the poor, and minorities, that are among the fastest growing elements within the U.S. population. According to a recent report from the APA, loneliness and social isolation may represent a greater public health hazard than obesity, and their impact has been growing and will continue to grow. While the psychological impact of isolation has been well described, little is known about the structural and neurochemical effects that occur in the brain following isolation. One of the big problems is that these questions are difficult to examine in human populations. For example: What changes in brain structure and function occur in individuals exposed to such conditions? How do the effects of isolation change with the duration of isolation? Does the age in which isolation occurs affect the extent of change? Are there methods by which isolated individuals can be reintroduced into a more social environment that will reduce/reverse any isolation-induced neurobiological consequences? It is for these reasons that we will make use of animal models that mimic four different conditions in which humans are grouped, including, mice housed singly in a “shoe box cage”, which we will refer to as “isolated housing” (IH, modeling total social isolation, i.e. solitary confinement), mice housed singly in a “shoe box cage” but with access to aspects of enrichment (exercise wheels and/or manipulatibles) that we refer to as “enhanced housing” (EH, modeling care in nursing facilities in which the person is oft times alone but gets access to therapy), mice housed in group conditions (4 mice) in a “shoe box cage” which we call standard housing (SH, modeling that if individuals housed in either assisted living communities or those individuals housed within a general population during incarceration) and groups of 14 mice housed in large cages (1 meter x 1 meter) with access to voluntary exercise, mazes, and toy/manipulatibles that we refer to as an “enriched environment” (EE, modeling a normal environment).

But before considering our proposal on isolation, however, it is important to ask whether observations made using animal models can inform us about any humancondition. We believe that there are several reasons to answer in the affirmative. First, rodents such as mice, like humans, are social animals preferring group over isolatedliving conditions. Second, the overwhelming majority of the human genome is nearly identical to that of the mouse. For example, of the 30,000 genes identified in C57BL/6 mice, 99% have a human equivalent. Third, the basic neuroanatomy of the mouse strongly parallels that of the human, differing mainly in the relative size of specific structures. Fourth, the key molecules that underlie neuronal plasticity are each essentially identical between the two species, including the monoamines and related enzymes, the NTFs, such as BDNF and GDNF. These similarities also exist in mechanisms for handling oxidative stress and inflammation.

Existing research indicates that there are enormous differences between rodents moved from the equivalent of a SH condition to an EE versus those maintained in “standard conditions”. Briefly, when compared to those from EE-raised, rats and mice reared in an impoverish environment show (a) deficits in learning and memory, (b) decreased neuronal complexity, (c) decrease in the number of blood vessels in brain, and (d) increase in susceptibility to several brain and behavioral conditions that emulate human diseases and psychiatric disorders, including AD and other neurodegenerative disorders, stroke, and schizophrenia. Additionally, a small but significant literature further suggests that rodent experiments are likely to be highly relevant to non-human primates. However, much of what we understand about environmental effects on the brain have been carried out in animals that were raised in an IH (or at best an SH) and then moved into an enriched environment. Our studies examining isolation better mimic the conditions of housing in humans, i.e. animals are born and raised in an EE and then later in life moved to a less enriched or completely isolated environment.

Studies in our labs support the hypothesis that housing can significantly influence brain structure and function. We examined two gross morphological features, total cell volume and total dendrite length, in neurons located in three regions of CNS from C57BL/6J mice raised in EE compared to those raised in an IH. In hippocampus, we found that pyramidal neurons from mice raised in isolation were smaller (less total volume, p≤0.01) and had reductions in their total dendrite length (p≤0.05). In the cerebral cortex, we examined layer V pyramidal cells and found similar reductions in these anatomical parameters. Conversely, we found that isolation increased the size and branching of hippocampal dentate gyrus neurons (Fig 5).

We have also examined if housing conditions can affect neurotransmitter and growth factor levels in brain, particularly in regions affected in Parkinson’s disease. We found that mice raised in the IH had lower levels of striatal dopamine as well as its metabolites DOPAC and HVA. We also have found that rats housed in an IH have reduced DA turnover and lower levels of phosphorylated TH. we also examined We examined mRNA expression of a number of growth factors, including BDNF, GDNF and IGF-1 in the basal ganglion of C57BL/6J mice raised in IH and EE. After 3 mo, mice raised in the IH had lower relative mRNA expression levels of BDNF (44% of EE mice, p<0.05, n=4), while GDNF was reduced 24% and IGF-1 increased 10% (both non-significant, n=4).