Effect of electrical stimulation of the infralimbic and prelimbic cortices on anxiolytic-like behavior of rats during the elevated plus-maze test, with particular reference to multiunit recording of the behavior-associated neural activity
Introduction
Fear and anxiety often disturb the activities of daily living and sometimes require concerted coping strategies to preserve the quality of life. Although the amygdala has been identified as an important brain region in emotional processing [[1], [2], [3], [4]], playing a role in the expression of fear and anxiety [[5], [6], [7], [8], [9]], the neural mechanisms underlying the process of overcoming fear and anxiety remain unclear. The medial prefrontal cortex (mPFC) has direct projections to the amygdala and is thought to regulate its activity [10]. Lesion or inactivation of the mPFC modify fear- and anxiety-like behavioral responses in rodents; however, the nature of this effect is somewhat controversial. For example, Jinks and McGregor [11] reported that lesion of the mPFC inhibits coping behavior in rats exposed to the threating or aversive environment in the elevated plus-maze test; similarly, Lisboa et al. [12] showed that pharmacological inactivation of the mPFC enhances anxiety-like behavior in rats submitted to the elevated plus-maze. In contrast, Shar and Treit [13,14] reported that lesion and pharmacological inactivation of the mPFC produces anxiolytic-like effects in the elevated plus-maze test. Hamani et al. [15] demonstrated that electrical activation of the mPFC induces antidepressant-like effects in the forced swimming test, while Scopinho et al. [16] found that pharmacological inactivation of the mPFC induces an antidepressant-like effect in this paradigm. Although these reports are not in agreement, they suggest that the mPFC functions as the neural basis for the control of fear and anxiety.
The mPFC is a heterogeneous structure. The ventral mPFC includes the infralimbic cortex (IL) and prelimbic cortex (PL), which have different projections to the amygdala. Whereas IL fibers project to widespread areas of the amygdala, PL fibers primarily project to the central and basolateral nuclei [10]. Electrophysiological studies of fear conditioning have shown that increased firing of IL neurons correlates with the recall of extinction learning, whereas increased firing of PL neurons correlates with sustained fear [[17], [18], [19]]. A study using intracortical stimulation similarly showed that IL stimulation decreases freezing behavior in response to a conditioned tone, whereas PL stimulation increases freezing behavior [20]. These studies of fear conditioning suggest that the IL and PL exert distinct functions with regard to fear and anxiety.
The purpose of the present study was to determine the roles of the IL and PL in anxiolytic-like behavioral effects. We investigated behavioral responses to electrical stimulation of the IL and PL and the neural activity of the respective neurons in rats during the elevated plus-maze test. We hypothesized that activation of the IL is associated with anxiolytic-like responses, whereas the activation of the PL is associated with anxiety-like responses.
Section snippets
Subjects
We used a total of 136 male Sprague-Dawley rats (Japan SLC, Inc., Shizuoka, Japan) that were 9–12 weeks of age at the time of testing: 77 rats were used to investigate behavioral responses to electrical stimulation of the IL and PL, and 59 rats were used to examine the neural activity of IL and PL neurons in the elevated plus-maze test. They were group-housed in a room with controlled temperature (24 °C) on a reverse 12-h light/dark cycle (lights on at 20:00 h) with food and water available ad
Histology
The tip positions of the stimulating electrodes in experiment 1 and the recording electrodes in experiment 2 were examined in coronal sections. The borders between the IL and PL were delimited based on the cytoarchitectonic features described by Krettek and Price [30]: the IL was characterized by relatively indistinct lamination and an uneven border between layer I and layer II, whereas the PL was characterized by a well-defined lamination, in which layer V contained large dark stained cells
Discussion
The present study demonstrated that IL stimulation induces a significant increase in the percentage of time spent and entries in the open arms of the elevated plus-maze compared to PL stimulation or no stimulation. In some cases, the stimulation applied to the ventral PL also increased the percentage of time spent and entries in the open arms. Several studies have reported that the dorsal and ventral portions of the PL show different connectivity [[31], [32], [33], [34]], distribution of
Conclusions
Our study showed that IL stimulation exerts anxiolytic-like effects, evidenced by a higher percentage of time spent and entries in the open arms of the maze; this was not observed during PL stimulation or no stimulation. Multiunit activity recordings from the IL and PL indicated an increased firing rate of IL neurons 1–3 s prior to entries from a closed to an open arm, whereas no significant changes were observed for PL neurons. These findings suggest that the IL plays a key role in exerting
Acknowledgments
This work was supported by Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (JSPS) to A.M. (KAKENHI 17H02121) and a Grant-in-Aid for JSPS Fellows to T.S. (267534). The authors thank Mei Ito and Saki Ito for their excellent assistance with animal experiments.
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2019, Behavioural Brain ResearchCitation Excerpt :The meaning of an increase in inhibitory responsivity of LSN-PL and LSN-IL connections may be revealed by the following observations. Activation studies have shown that although electrical stimulation of the PL produces some similar actions, stimulation of the IL produces an increase in the number of entries into the open arms of the elevated plus maze, and multiple-unit activity in the IL indicates an increase in firing rate in the IL before entries into the open arm [59]. Fear conditioning with footshock stress produces a short increase in neuronal firing in the PL, followed by recovery.