Double dissociation of function within the hippocampus: Spatial memory and hyponeophagia.

Bannerman, David M.; Deacon, R. M. J.; Offen, Shani; Friswell, J.; Grubb, Matthew S.; Rawlins, J. N. P.

doi:10.1037//0735-7044.116.5.884

Cited by 87 publications

(6 citation statements)

References 53 publications

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“…To assess the resulting changes in brain AMPK activity, we utilized western blot analysis after sacrifice of RSD mice. We targeted two limbic brain regions for this analysis: the mPFC [ 32 , 33 ] and the ventral hippocampus (vHPC) [ 34 , 35 ], both of which significantly regulate anxiety in both rodent and human subjects. The analysis showed a marked decrease in the level of p-AMPK (T172 phosphorylation) in the mPFC of RSD mice compared to control mice, while no discernible difference was noted in the vHPC (Fig.…”

Section: Resultsmentioning

confidence: 99%

Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons

Zhang,

Zong,

et al. 2023

Mol Psychiatry

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Diabetic patients receiving the antidiabetic drug metformin have been observed to exhibit a lower prevalence of anxiety disorders, yet the precise mechanism behind this phenomenon is unclear. In our study, we found that anxiety induces a region-specific reduction in AMPK activity in the medial prefrontal cortex (mPFC). Concurrently, transgenic mice with brain-specific AMPK knockout displayed abnormal anxiety-like behaviors. Treatment with metformin or the overexpression of AMPK restored normal AMPK activity in the mPFC and mitigated social stress-induced anxiety-like behaviors. Furthermore, the specific genetic deletion of AMPK in the mPFC not only instigated anxiety in mice but also nullified the anxiolytic effects of metformin. Brain slice recordings revealed that GABAergic excitation and the resulting inhibitory inputs to mPFC pyramidal neurons were selectively diminished in stressed mice. This reduction led to an excitation-inhibition imbalance, which was effectively reversed by metformin treatment or AMPK overexpression. Moreover, the genetic deletion of AMPK in the mPFC resulted in a similar defect in GABAergic inhibitory transmission and a consequent hypo-inhibition of mPFC pyramidal neurons. We also generated a mouse model with AMPK knockout specific to GABAergic neurons. The anxiety-like behaviors in this transgenic mouse demonstrated the unique role of AMPK in the GABAergic system in relation to anxiety. Therefore, our findings suggest that the activation of AMPK in mPFC inhibitory neurons underlies the anxiolytic effects of metformin, highlighting the potential of this primary antidiabetic drug as a therapeutic option for treating anxiety disorders.

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Section: Resultsmentioning

confidence: 99%

Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons

Zhang,

Zong,

et al. 2023

Mol Psychiatry

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“…The ventral hippocampus (VH) and associated cortices are important substrates for aversive contextual processes, such as the acquisition and expression of aversive contextual associations [8][9][10][11], the contextually-mediated renewal of previously-extinguished aversive CSs [12][13][14][15], and context-dependent instrumental avoidance [16][17][18]. VH is also required for classic anxiety-like behaviors, in which animals organize their exploratory behavior to minimize contact with threatening aspects of an experimental apparatus [19][20][21][22][23]. These results are consistent with the proposal that VH contains a map that links interior representations of aversive states with environmental stimuli [24].…”

Section: Introductionmentioning

confidence: 99%

Ventral hippocampus mediates inter-trial responding in signaled active avoidance

Oleksiak,

Plas,

Carriaga

et al. 2024

Preprint

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The hippocampus has a central role in regulating contextual processes in memory. We have shown that pharmacological inactivation of ventral hippocampus (VH) attenuates the context-dependence of signaled active avoidance (SAA) in rats. Here, we explore whether the VH mediates intertrial responses (ITRs), which are putative unreinforced avoidance responses that occur between trials. First, we examined whether VH inactivation would affect ITRs. Male rats underwent SAA training and subsequently received intra-VH infusions of saline or muscimol before retrieval tests in the training context. Rats that received muscimol performed significantly fewer ITRs, but equivalent avoidance responses, compared to controls. Next, we asked whether chemogenetic VH activation would increase ITR vigor. In male and female rats expressing excitatory (hM3Dq) DREADDs, systemic CNO administration produced a robust ITR increase that was not due to nonspecific locomotor effects. Then, we examined whether chemogenetic VH activation potentiated ITRs in an alternate (non-training) test context and found it did. Finally, to determine if context-US associations mediate ITRs, we exposed rats to the training context for three days after SAA training to extinguish the context. Rats submitted to context extinction did not show a reliable decrease in ITRs during a retrieval test, suggesting that context-US associations are not responsible for ITRs. Collectively, these results reveal an important role for the VH in context-dependent ITRs during SAA. Further work is required to explore the neural circuits and associative basis for these responses, which may be underlie pathological avoidance that occurs in humans after threat has passed.

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“…Since the septo-hippocampal system was first theorized to mediate a behavioral inhibition system (BIS) that is activated to suppress approach responses under conflict situations ( Gray and McNaughton, 2000 ), converging cross-species empirical evidence has highlighted a critical role for the ventral (rodent) or anterior (primate), but not dorsal/posterior portion of the hippocampus (HPC), in modulating anxiety and AA responding during high motivational conflict ( Ito and Lee, 2016 ). For example, in addition to increasing anxiolytic behavior in rodents, lesion or pharmacological inactivation of the ventral HPC (vHPC) increases approach behaviors to motivationally conflicting learned stimuli ( Bannerman et al, 2014 ; Bannerman et al, 2003 ; Bannerman et al, 2002 ; Schumacher et al, 2018 ; Schumacher et al, 2016 ; Yeates et al, 2020 ). Similarly, human functional magnetic resonance imaging (fMRI) and patient neuropsychological studies with analogous AA tasks have revealed anterior HPC involvement when participants experience high AA conflict ( Bach et al, 2014 ; O’Neil et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, the HPC is implicated in scene and context-based processing, while the PRC is predominantly involved in object-associated processes, both within the domain of memory and even beyond ( Graham et al, 2010 ; Murray et al, 2007 ; Zeidman and Maguire, 2016 ). Since ethological anxiety tasks and paradigms of AA conflict processing have typically employed spatial stimuli (e.g., scene images) or required environmental exploration (e.g., maze navigation) ( Bach et al, 2014 ; Bannerman et al, 2002 ; O’Neil et al, 2015 ; Schumacher et al, 2018 ; Schumacher et al, 2016 ), it raises the question of whether the HPC plays a ubiquitous role in AA conflict processing across all stimulus domains or whether other MTL structures may also play a critical role depending on the stimuli involved.…”

Section: Introductionmentioning

confidence: 99%

Male rodent perirhinal cortex, but not ventral hippocampus, inhibition induces approach bias under object-based approach-avoidance conflict

Dhawan

Pinter

Lee

et al. 2023

eLife

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Neural models of approach-avoidance (AA) conflict behavior and its dysfunction have focused traditionally on the hippocampus, with the assumption that this medial temporal lobe (MTL) structure plays a ubiquitous role in arbitrating AA conflict. We challenge this perspective by using three different AA behavioural tasks in conjunction with optogenetics, to demonstrate that a neighbouring region in male rats, perirhinal cortex, is also critically involved but only when conflicting motivational values are associated with objects and not contextual information. The ventral hippocampus, in contrast, was found not to be essential for object-associated AA conflict, suggesting its preferential involvement in context-associated conflict. We propose that stimulus type can impact MTL involvement during AA conflict and that a more nuanced understanding of MTL contributions to impaired AA behaviour (e.g., anxiety) is required. These findings serve to expand upon the established functions of the perirhinal cortex while concurrently presenting innovative behavioural paradigms that permit the assessment of different facets of AA conflict behaviour.

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Double dissociation of function within the hippocampus: Spatial memory and hyponeophagia.

Cited by 87 publications

References 53 publications

Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons

Anxiolytic effect of antidiabetic metformin is mediated by AMPK activation in mPFC inhibitory neurons

Ventral hippocampus mediates inter-trial responding in signaled active avoidance

Male rodent perirhinal cortex, but not ventral hippocampus, inhibition induces approach bias under object-based approach-avoidance conflict

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