Innovations in Methodology: Depression Research and Learned Helplessness

Learned helplessness is a classic model of depression first described in 1968 by psychologists Steven F. Maier and Martin Seligman. Since then, learned helplessness has been studied extensively as a model for depression, addictive behavior, and even abuse victims. The behavior of learned helplessness has been described in humans as well as in animals, underscoring the importance of animal models in translational research.

In one experimental model of learned helplessness, an animal is subjected to an aversive stimulus from which it cannot escape. Later, the animal is exposed to the same aversive stimulus, but this time, an escape route is also made available. When given the opportunity to escape an aversive stimulus, animals that had previous exposure to an inescapable aversive stimulus typically fail to escape, or take substantially longer to escape than naive animals. This phenotype has been interpreted as an experimental indication of learned helplessness. Experiments such as these are usually performed using an active avoidance procedure in a two-chamber shuttle box, with a removable door placed between the chambers.

Since clinical treatment of depression remains incomplete, scientists continue to explore the neurobiological mechanisms of the disorder. Interestingly, the hippocampus, responsible for the consolidation of memories for long-term storage, appears to be a player in depression. Hippocampal atrophy and impairment of hippocampal functions have been reported in patients with major depressive disorder (Malberg et al., 2000; Sheline et al., 1999; Stockmeier et al., 2004). Recent work from Hajszan et al., 2009 corroborates this finding in rats by demonstrating a decrease in the number of synaptic spines in the hippocampi of helpless animals when compared with non-stressed animals. These changes in neuro-anatomy are also associated with changes in behavior: rats with fewer synaptic spines show a more severe helpless phenotype.

More recently, Miettinen et al.(2012) sought to further characterize the loss of hippocampal synaptic spines in helpless animals. A major unresolved issue was to determine if pyramidal cells, important for hippocampal signaling and often the focus of neural plasticity studies, are lost completely, or if the reduction in synaptic spines is occurring at the level of the synapse and is thus plastic. Claiming that the current methodology used to study the cellular structure of the hippocampus is insufficient to maintain its 3-dimensional structure, the authors sought to develop a new approach. Using a combination of osmium tetroxide treatment and Durcupan-embedding, the authors managed to maintain the structure of the hippocampus, yielding stable samples suitable for electron microscopy, more reliable cell counting, and delineation of important hippocampal regions. Using the new technique, the study reported no changes in the number of pyramidal cells or in the overall volume of hippocampus, noting that the changes in number of synaptic spines were indeed occurring only at the synapses themselves, suggesting that neuronal plasticity may be involved.

The hippocampus is likely a truly important area for research in depression. Cellular changes in the hippocampus occur in patients with depressive disorder, as well as other neurodegenerative disease, including Alzheimer’s disease. The observation that neuronal plasticity may underlie these changes has important implications for the treatment of depression.

Questions for Neuroscientists:

-What do you feel is the best animal model for depression?

-What are the strengths and weaknesses of the Active Avoidance paradigm?

-How can plasticity in the hippocampus be studied?

Further Reading:

Hajszan T, Dow A, Warner-Schmidt JL, Szigeti-Buck K, Sallam NL, Parducz A, Leranth C, Duman RS. (2009). Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression. Biol Psychiatry. Mar 1; 65(5):392-400.



Malberg JE, Eisch AJ, Nestler EJ, Duman RS. (2000). Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci Dec 15; 20(24):9104-10.



Miettinen R, Hajszan T, Riedel A, Szigeti-Buck K, Leranth C. (2012). Estimation of the total number of hippocampal CA1 pyramidal neurons: New methodology applied to helpless rats. J Neurosci Methods. Mar 30; 205(1):130-8.



Seligman ME, Maier SF, Geer JH. (1968). Alleviation of learned helplessness in the dog. J Abnorm Psychol. Jun; 73(3):256-62.



Sheline YI, Sanghavi M, Mintun MA, Gado MH. (1999). Depression duration but not age predits hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. Jun 15; 19(12):5034-43.



Stockmeier CA, Mahajan GJ, Konick LC, Overholser JC, Jurjus GJ, Meltzer HY, Uylings HB, Friedman L, Rajkowska G. (2004). Cellular changes in the postmortem hippocampus in major depression. Biol Psychiatry. Nov 1; 56(9):640-650.

