The brainstem, wedged between the spinal cord and the cortex, collects sensory input and distributes it throughout the brain, where it affects all manner of cognitive processing. For example, input from the brainstem’s locus coeruleus to the hippocampus shapes memory formation, and early pathology in the LC contributes to memory loss in Alzheimer’s disease. A study in the May 24 Science traced a new line of communication between the brainstem and the hippocampus, and showed that it, too, plays a critical role in memory formation. The work, from Gábor Nyiri and colleagues at the Hungarian Academy of Sciences, Budapest, reveals that neurons in the nucleus incertus connect to, and regulate the activity of, memory-storing CA1 interneurons in the hippocampus. Optogenetic activation of nucleus incertus GABAergic neurons prevented formation of fear memories in mice, while inhibition enhanced fear recall. The pathway may be involved in anxiety or stress disorders.
- Brainstem’s nucleus incertus translates sensory input into GABAergic inhibition of hippocampal interneurons.
- This helps set the strength and specificity of fear memories in mice.
- Potential for role in dementia remains to be seen.
“This study adds more evidence to the fascinating role of evolutionarily ancient brainstem nuclei, such as the locus coeruleus and the nucleus incertus in higher-order cognitive functions,” wrote Heidi Jacobs, Maastricht University, The Netherlands, to Alzforum (full comment below).
Could NI dysfunction explain an aspect of dementia? There’s no direct evidence of that. Still, given the new data, “It is conceivable that dysfunction of NI GABAergic neurons may contribute to memory deficits as seen in Alzheimer’s disease,” according to Yadong Huang, University of California, San Francisco (full comment below).
The brainstem bears early signs of AD pathology. Phosphorylated tau protein appears in the locus coeruleus (LC) and is thought to spread from there (reviewed in Weinshenker 2018). Dysfunction and degeneration of LC neurons likely contributes to symptoms of AD. The same is true for Parkinson’s disease, where α-synuclein inclusions collect early on in the LC.
The nucleus incertus, on the other hand, has not been identified as a site of pathology, or linked to changes in brain connectivity or cognition in AD. Packed with GABAergic projection neurons, the NI modulates hippocampal theta rhythms, which are linked to learning and memory.
In the new study, first author András Szőnyi and colleagues drew on an arsenal of techniques, including tract tracing, immunogold receptor labeling and electrophysiological recording, to establish that NI GABAergic neurons directly and indirectly inhibit the firing of CA1 somatostatin-containing interneurons in the hippocampus. These interneurons, in turn, determine whether memory engrams are successfully encoded by pyramidal neurons. Environmental stimuli, especially noxious air puffs or rewarding sips of water, activated the NI neurons, suggesting the neurons might play a role in context-dependent memory formation, such as when mice learn to associate a painful shock with a specific locale.
To prove this, the scientists expressed light-responsive channels in GABAergic NI cells by way of optogenetics. They induced a contextual fear memory in mice by moving the animals from their home cage to a new environment, where the mice received a series of electric foot shocks. A day later, mice placed in the same environment froze in fear, anticipating a foot shock. If the researchers used light to activate NI neurons at the time of the foot shock, the mice did not make the fear memory and did not freeze in the new environment the next day. If the researchers inhibited NI activity, the mice seemed excessively scared, freezing for longer than control mice. This is consistent with what’s seen in NI-lesioned rats who display pathologically exaggerated fear memories (Pereira et al., 2013).
The results suggest the NI acts via interneurons to fine-tune pyramidal cell recruitment, ensuring that the correct number of them form a memory. If the NI is overly active, too many pyramidal cells encode a memory and it does not stick, as in the fearless mice. When the NI is sluggish, too fewvpyramidal cells get involved and result is a stronger generalized fear, as in the NI-lesioned animals.
“The disruption of hippocampal theta and learning by targeted intervention in the brainstem GABAergic inputs is compelling. It will be interesting to know if other behaviors are affected,” said Steven Mennerick, Washington University in St. Louis.
The authors speculate that hyperactivity of NI might be linked to dementia, where memory formation is impaired. That has not been shown. “This is a nice study demonstrating NI GABAergic neurons bi-directionally regulate fear memory via somatostatin-positive interneurons in the hippocampus. Concerning a potential link to dementia, we will need to know if these neurons are dysregulated in dementia-related disorders,” said Li-Huei Tsai, MIT, Cambridge, Massachusetts.
Nyiri told Alzforum he does not believe that the function of NI has ever been tested in dementia or in any Alzheimer’s model. “But we know that prefrontal cortex is affected in Alzheimer’s disease, and we found that it projects onto NI GABAergic cells. Overactivity or degeneration of these inputs to the NI may have serious adverse consequences in memory formation, similar to that described in the paper,” he said.—Pat McCaffrey
- Weinshenker D. Long Road to Ruin: Noradrenergic Dysfunction in Neurodegenerative Disease. Trends Neurosci. 2018 Apr;41(4):211-223. Epub 2018 Feb 20 PubMed.
- Pereira CW, Santos FN, Sánchez-Pérez AM, Otero-García M, Marchioro M, Ma S, Gundlach AL, Olucha-Bordonau FE. Electrolytic lesion of the nucleus incertus retards extinction of auditory conditioned fear. Behav Brain Res. 2013 Jun 15;247:201-10. Epub 2013 Mar 26 PubMed.
No Available Further Reading
- Szőnyi A, Sos KE, Nyilas R, Schlingloff D, Domonkos A, Takács VT, Pósfai B, Hegedüs P, Priestley JB, Gundlach AL, Gulyás AI, Varga V, Losonczy A, Freund TF, Nyiri G. Brainstem nucleus incertus controls contextual memory formation. Science. 2019 May 24;364(6442) PubMed.