Research reportFurther evidence that anxiety and memory are regionally dissociated within the hippocampus
Introduction
The hippocampus has a long established-role in spatial learning and memory [24], [28]. It may also regulate defensive behaviors related to anxiety [4]. Electrolytic or excitotoxic lesions of the hippocampus produce anxiolytic-like behaviors in elevated mazes and social interaction tests [2], [10]. Moreover, it is proposed that anxiolytic-like drugs induce their effects by acting on a behavioral inhibition system that includes the hippocampus [15].
There is considerable evidence to suggest that the hippocampus may be differentiated into dorsal (DH) and ventral (VH) poles [4], [27]. The precise contribution of these two regions on anxiety and memory, however, still remains a matter of debate. With regard to the former process, research has frequently focused on avoidance behavior scored in the elevated plus-maze (EPM) test. Microinjection of the benzodiazepine midazolam into the DH decreased this response [19], [20]. However, anxiolytic-like effects were also reported after either excitotoxic or electrolytic lesions of the VH, but not the DH [16]. VH lesions also reduced anxiety-related responses in the social interaction, the light/dark, the elevated T-maze and the cat-odor exposure tests [18], [26], [32]. These findings suggest that defensive behaviors related to anxiety are preferentially regulated by the VH. In relation to spatial learning aspects, a wealth of evidence suggests that it depends preferentially on DH function [4], [21]. For instance, the degree of impairment of spatial learning in a water-maze correlates with DH, but not VH lesions [22], [23], [33].
The objective of the present study was to further investigate a possible hippocampal regional dissociation regarding the modulation of anxiety and memory processes. Since prior studies have usually assessed this issue by using lesion techniques, the current study adopted acute bilateral lidocaine microinfusion into the VH or the DH to transiently interfere with normal hippocampal activity. In addition, since behavioral measures related to anxiety and memory has been usually assessed by different tests, the present study used the EPM Trial 1/2 protocol. In the EPM test, after the initial (Trial 1) exploration of the whole apparatus, rodents express increased inhibitory avoidance response during retesting (Trial 2). This latter finding is thought to reflect the acquisition of spatial memory related to exploration of potentially dangerous areas of the maze—the open-arms [6], [9]. This approach, therefore, was selected based on its capacity of evaluating either anxiety- and memory-related behavioral responses. Our hypothesis is that lidocaine microinfusion into the VH would interfere with the former whereas the latter responses would be prudentially affected by DH inactivation.
Section snippets
Animals
One-hundred and fifty-five male Wistar rats weighing 250–270 g at the time of testing were housed in pairs in a temperature-controlled room (23 ± 1 °C), under standard laboratory conditions with free access to food and water, and with a 12 h light/12 h dark cycle (lights on at 06:30 h a.m.). Procedures were conducted in conformity with the Brazilian Society of Neuroscience and Behavior guidelines for the care and use of laboratory animals, which are in compliance with international laws and politics.
Results
Pictures showing representative injection sites into the VH and the DH can be seen in Fig. 1. Animals receiving microinjections outside these hippocampal poles (27% and 14%, respectively) were excluded from the analysis.
Discussion
The main experimental findings of the present study are that: (1) lidocaine injected into the VH prior to Trial 1 increased open-arm exploration. No effect was found, however, when the same treatment was given at post-Trial 1 or pre-Trial 2 and (2) lidocaine injected into the DH reduced the open-arm avoidance when given at pre-Trial 2, but not at pre-Trial 1 or post-Trial 1.
These findings are consistent with studies implicating the VH, but not the DH, in the regulation of anxiety-related
Acknowledgments
This work was supported by FAPESP (02/13197-2; 03/13032-6; 04/13197-4). The authors also thank A.P. Padovan, D.C. de Aguiar and J.C. de Aguiar for technical assistance.
References (33)
- et al.
Ventral hippocampal lesions affect anxiety but not spatial learning
Behav Brain Res
(2003) - et al.
Regional dissociations within the hippocampus-memory and anxiety
Neurosci Biobehav Rev
(2004) - et al.
Previous maze experience required to increase open arms avoidance in rats submitted to the elevated plus-maze model of anxiety
Behav Brain Res
(2000) - et al.
Ethological and temporal analyses of anxiety-like behavior: the elevated plus-maze model 20 years on
Neurosci Biobehav Rev
(2005) - et al.
Anxiety is functionally segregated within the septo-hippocampal system
Brain Res
(2004) - et al.
Effects of centrally administered anxiolytic compounds in animal models of anxiety
Neurosci Biobehav Rev
(1999) - et al.
The anxiolytic effects of intra-hippocampal midazolam are antagonized by intra-septal 1-glutamate
Brain Res
(2001) - et al.
Effective spread and time course of neural inactivation caused by lidocaine injection in monkey cerebral cortex
J Neurosci Method
(1997) - et al.
Lesions of the ventral hippocampus, but not the dorsal hippocampus, impair conditioned fear expression and inhibitory avoidance on the elevated T-maze
Neurobiol Learn Mem
(2004) - et al.
Dissociation of function within the hippocampus: effects of dorsal, ventral and complete excitotoxic hippocampal lesions on spatial navigation
Neuroscience
(2004)
Hippocampal formation
Double dissociation of function within the hippocampus: spatial memory and hyponeophagia
Behav Neurosci
Scopolamine given pre-Trial 1 prevents the one-trial tolerance phenomenon in the elevated plus-maze Trial 2
Behav Pharmacol
Conservation of hippocampal memory function in rats and humans
Nature
Anxiolytic effects of cytotoxic hippocampal lesions in rats
Behav Neurosci
Cited by (104)
The impact of maternal immune activation on GABAergic interneuron development: A systematic review of rodent studies and their translational implications
2024, Neuroscience and Biobehavioral ReviewsAnxiety and Alzheimer's disease: Behavioral analysis and neural basis in rodent models of Alzheimer's-related neuropathology
2021, Neuroscience and Biobehavioral ReviewsChemogenetic inhibition of ventral hippocampal CaMKIIα-expressing neurons attenuates anxiety- but not fear-like defensive behaviors in male Long-Evans hooded rats
2021, Neuroscience LettersCitation Excerpt :Pentkowski and colleagues reported that excitotoxic vHC but not dHC lesions reduce defensive behaviors in rats exposed to cat odor, but not a live cat, effects suggesting a specific role for the vHC in regulating anxiety- but not fear-like defensive states [22]. Reduced anxiety-like behavior has also been observed in the EPM following vHC lesions/inactivation using lidocaine [23], ibotenic acid [24], tetrodotoxin [25] and electrolytic lesions [26]. Collectively, these finding highlight the vHC as a pivotal neural correlate modulating anxiety-like defensive behaviors in rats.