Summary: Study reveals how the amygdala plays a role in pre-pulse inhibition by activating inhibitory neurons in the brain stem of mice. The findings could have positive implications in the development of treatments for schizophrenia, OCD, and other disorders marked with impaired somatosensory gating.
We’re all familiar with the startle reflex – that sudden, uncontrollable jerk that occurs when we’re surprised by a noise or other unexpected stimulus. But the brain also has an important pre-attentive mechanism to tamp down that response and tune out irrelevant sounds so you can mind the task in front of you.
This pre-attentive mechanism is called sensorimotor gating and normally prevents cognitive overload. However, sensorimotor gating is commonly impaired in people with schizophrenia and other neurological and psychiatric conditions, including post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD).
“Reduced sensorimotor gating is a hallmark of schizophrenia, and this is often associated with attention impairments and can predict other cognitive deficits,” explains neurologist Karine Fénelon, assistant professor of biology at the University of Massachusetts Amherst.
“While the reversal of sensorimotor gating deficits in rodents is a gold standard for antipsychotic drug screening, the neuronal pathways and cellular mechanisms involved are still not completely understood, even under normal conditions.”
To assess sensorimotor gating, neuroscientists measure prepulse inhibition (PPI) of the acoustic startle reflex. PPI occurs when a weak stimulus is presented before a startle stimulus, which inhibits the startle response.
For the first time, Fénelon and her UMass Amherst team – then-Ph.D. student Jose Cano (now a postdoctoral researcher at the University of Rochester Medical Center) and Ph.D. student Wanyun Huang – have shown how the amygdala, a brain region typically associated with fear, contributes to PPI by activating small inhibitory neurons in the mouse brain stem.
This discovery, published in the journal BMC Biology, advances understanding of the systems underlying PPI and efforts to ultimately develop medical therapies for schizophrenia and other disorders by reversing pre-attentive deficits.
“Until recently, prepulse inhibition was thought to depend on midbrain neurons that release the transmitter acetylcholine,” Fénelon explains. “That was because studies of schizophrenia patients involved deficits in the cholinergic system.”
But there exists a “super cool neuroscience tool” – optogenetics – which allows scientists to use light to pinpoint and control genetically modified neurons in various experimental systems. “It is very specific,” Fénelon says. “Before this, we couldn’t pick and choose which neurons to manipulate.”
Their challenge was to use optogenetics to identify which circuits in which parts of the brain were involved in PPI. “We wanted to know what brain region connects to the core of the startle inhibition circuit in the brain stem, so we put tracers or dye to visualize those neurons,” Fénelon says. “With this approach we were able to identify amygdala neurons connected to the brain stem area in the center of the startle inhibition circuit.”
Next, they tested with optogenetic tools whether this connection between the amygdala and the brain stem was important for startle inhibition. “We know that in the brain of schizophrenia patients the function of the amygdala is also altered, so it made sense to us that this brain region was relevant to disease,” Fénelon says.
By photo-manipulating amygdala neurons in mice, they showed that the amygdala appeared to contribute to PPI by activating brain stem inhibitory, or glycinergic, neurons. Specifically, PPI was reduced by either shutting down the excitatory synapses between the amygdala and the brain stem or by silencing the brain stem inhibitory neurons themselves. “Interestingly, the PPI reduction measured as a result of these photo manipulations mimicked the PPI reduction observed in humans with schizophrenia and in mouse models of schizophrenia,” Fénelon says.
To better detail this connection, Fénelon and team used electrophysiology along with optogenetics to record the electrical activity of individual neurons taken from thin brain sections, in vitro. “This very precise yet technically challenging recording method allowed us to confirm without any doubt that amygdala excitatory inputs activate those glycinergic neurons in the brain stem,” Fénelon says.
She calls this finding “a piece of the puzzle” that pinpoints the prepulse inhibition circuit. Now she’s working in her lab using this new information to identify other brain pathways and attempt to reverse pre-attentive deficits in a mouse model of schizophrenia. Such a breakthrough would allow researchers to begin to develop drugs that can more precisely target treatment of pre-attentive problems.
About this neuroscience research news
Source: UMass Contact: Patty Shillington – UMass Image: The image is credited to UMass Amherst
The amygdala modulates prepulse inhibition of the auditory startle reflex through excitatory inputs to the caudal pontine reticular nucleus
Sensorimotor gating is a fundamental pre-attentive process that is defined as the inhibition of a motor response by a sensory event. Sensorimotor gating, commonly measured using the prepulse inhibition (PPI) of the auditory startle reflex task, is impaired in patients suffering from various neurological and psychiatric disorders.
PPI deficits are a hallmark of schizophrenia, and they are often associated with attention and other cognitive impairments. Although the reversal of PPI deficits in animal models is widely used in pre-clinical research for antipsychotic drug screening, the neurotransmitter systems and synaptic mechanisms underlying PPI are still not resolved, even under physiological conditions.
Recent evidence ruled out the longstanding hypothesis that PPI is mediated by midbrain cholinergic inputs to the caudal pontine reticular nucleus (PnC). Instead, glutamatergic, glycinergic, and GABAergic inhibitory mechanisms are now suggested to be crucial for PPI, at the PnC level. Since amygdalar dysfunctions alter PPI and are common to pathologies displaying sensorimotor gating deficits, the present study was designed to test that direct projections to the PnC originating from the amygdala contribute to PPI.
Using wild type and transgenic mice expressing eGFP under the control of the glycine transporter type 2 promoter (GlyT2-eGFP mice), we first employed tract-tracing, morphological reconstructions, and immunohistochemical analyses to demonstrate that the central nucleus of the amygdala (CeA) sends glutamatergic inputs lateroventrally to PnC neurons, including GlyT2+ cells. Then, we showed the contribution of the CeA-PnC excitatory synapses to PPI in vivo by demonstrating that optogenetic inhibition of this connection decreases PPI, and optogenetic activation induces partial PPI. Finally, in GlyT2-Cre mice, whole-cell recordings of GlyT2+ PnC neurons in vitro paired with optogenetic stimulation of CeA fibers, as well as photo-inhibition of GlyT2+ PnC neurons in vivo, allowed us to implicate GlyT2+ neurons in the PPI pathway.
Our results uncover a feedforward inhibitory mechanism within the brainstem startle circuit by which amygdalar glutamatergic inputs and GlyT2+ PnC neurons contribute to PPI. We are providing new insights to the clinically relevant theoretical construct of PPI, which is disrupted in various neuropsychiatric and neurological diseases.