Summary: Excessive activity in a specific region of the brain—the hippocampus—has been associated with particular symptoms of schizophrenia.
Source: University of Nottingham
New research identifies a link between increased hippocampal activity and deficits in associative learning seen in schizophrenia, suggesting paths for more focused treatments.
A team at the University of Nottingham investigated how disrupted inhibitory signaling and abnormally high activity in the hippocampus affect behavior. Their experiments in rats show that reduced inhibition in the hippocampus—caused by impaired GABAergic neurotransmission—does not appear to interfere with the brain’s ability to filter out irrelevant information, a cognitive process often impaired in schizophrenia. Instead, this hippocampal over-activity selectively impairs associative learning, including forms of fear conditioning.
Associative learning deficits, such as those revealed by Pavlovian fear conditioning paradigms, are associated with the negative symptoms of schizophrenia. Negative symptoms include diminished motivation, flattened affect, and disruptions in emotional and reward processing. By clarifying which cognitive and behavioral processes are affected by hippocampal disinhibition, the study points toward more targeted approaches to treat specific symptom clusters in schizophrenia.
The study’s results have been published in the journal eNeuro.
Schizophrenia is a serious psychiatric condition. In the UK, around 220,000 people are receiving treatment for schizophrenia through the NHS at any given time. The disorder can present with three broad categories of symptoms: negative symptoms (such as apathy, social withdrawal and low energy), positive symptoms (including hallucinations and delusions), and cognitive symptoms (for example, problems with memory and attention). Individuals with schizophrenia may experience one, two, or all three types of symptoms concurrently.
Neurons communicate through chemical messengers known as neurotransmitters. Gamma-aminobutyric acid (GABA) is the brain’s primary inhibitory neurotransmitter and plays a vital role in restraining neural activity. Proper GABAergic inhibition prevents excessive firing and helps the brain ignore irrelevant stimuli. When GABA signaling is reduced, circuits can become overactive, which may underlie some symptoms observed in psychiatric disorders.
The hippocampus, located within the temporal lobes, is central to memory formation and emotional processing. The current research sheds light on how abnormal hippocampal activity specifically affects associative learning and fear conditioning—processes that are relevant to the negative and cognitive aspects of schizophrenia.
The study was led by post-doctoral researcher Stuart Williams. He explains that prior work has shown increased hippocampal activity in people with schizophrenia, and this study set out to understand how that over-activity manifests in behavior. Using a rat model, the team manipulated GABAergic inhibition in the hippocampus and measured effects on different behavioral tasks.
Williams and colleagues report that reducing inhibition in the hippocampus did not disrupt behaviors linked to filtering out irrelevant information—the cognitive process implicated in the development of hallucinations and delusions. However, hippocampal disinhibition did impair associative learning, specifically conditioned fear responses, indicating a potential contribution to negative symptoms such as diminished emotional responsiveness and impaired reward-related learning.
These findings have practical implications for developing treatments that target negative symptoms of schizophrenia. By identifying the behavioral consequences of increased hippocampal activity, researchers can better focus interventions that aim to normalize activity in specific brain regions rather than applying broad, non-specific treatments.
Stuart Williams adds that revealing detailed links between aberrant hippocampal activity and particular symptom domains helps to clarify how disruption of neural circuits contributes to the clinical picture of schizophrenia. Such insights may guide development of therapies intended to reduce hippocampal over-activity and thereby improve aspects of the disorder related to associative learning and motivation.
About this schizophrenia research news
Author: Press Office
Source: University of Nottingham
Contact: Press Office – University of Nottingham
Image: The image is in the public domain
Original Research: Open access.
“Hippocampal Disinhibition Reduces Contextual and Elemental Fear Conditioning While Sparing the Acquisition of Latent Inhibition” by Stuart A. Williams et al., eNeuro.
Abstract
Hippocampal Disinhibition Reduces Contextual and Elemental Fear Conditioning While Sparing the Acquisition of Latent Inhibition
Hippocampal neural disinhibition—characterized by reduced GABAergic inhibition—is a notable feature of schizophrenia pathophysiology. The hippocampus contributes to the neural circuits that govern fear conditioning and can influence prefrontal and striatal systems, including dopamine-related pathways involved in assigning salience to stimuli.
Because of these connections, hippocampal disinhibition could underlie impairments in fear conditioning and salience modulation reported in schizophrenia. To investigate this, the study examined the effects of ventral hippocampus (VH) disinhibition in male rats on fear conditioning and on latent inhibition (a measure of salience modulation) using a conditioned emotional response (CER) procedure. A flashing light served as the conditioned stimulus (CS), and conditioned suppression measured conditioned fear.
In the first experiment, disinhibition of the VH was achieved by infusing the GABA-A receptor antagonist picrotoxin prior to CS pre-exposure and conditioning. This manipulation substantially reduced fear conditioning to both the CS and the surrounding context. Latent inhibition was observable in saline-treated controls but could not be detected in picrotoxin-treated rats due to the overall low level of fear conditioning. In a second experiment, infusing picrotoxin only before CS pre-exposure did not alter acquisition of fear conditioning or latent inhibition. Together, these results indicate that VH disinhibition disrupts contextual and elemental fear conditioning while sparing the initial acquisition of latent inhibition.
The pattern of disrupted fear conditioning in the animal model mirrors aversive conditioning deficits reported in schizophrenia and suggests that hippocampal disinhibition may impair neural processing within the hippocampus and in its downstream targets. Understanding these circuit-specific effects offers a clearer path toward interventions that address particular symptom domains in schizophrenia.