Behavior: Prompting social investigation
A social memory pathway connecting the ventral hippocampus, the lateral septum and the ventral tegmental area helps to regulate how mice react to unknown individuals.
- Institute for Behavioral Genetics, University of Colorado Boulder, United States
- Department of Psychology and Neuroscience, University of Colorado Boulder, United States
- Crnic Institute Boulder Branch, BioFrontiers Institute, University of Colorado Boulder, United States
Animals often need to assess whether a member of their species (a conspecific) that they have not met before will be a friend or a foe. As such, most adult animals would tend to investigate an unfamiliar peer over one which they were already acquainted with (Tapper and Molas, 2020).
Deciding whether and how to engage with an unknown individual relies on multiple levels of analysis underpinned by different brain networks and areas. First, the animal must identify that it has not encountered this specific peer before. For this, it must detect and check discrete features in the new conspecific against information deposited in memory networks after previous encounters. Certain regions of the hippocampus (the brain structure that helps to form memory and process emotions) have been implicated in this mechanism. Hippocampal neurons in the CA2 region and in the ventral portion of the CA1 area, for example, store social memories that allow animals to distinguish between new and familiar conspecifics (Hitti and Siegelbaum, 2014; Okuyama et al., 2016).
Once an unknown conspecific has been identified, other brain areas are then required to determine the appropriate course of action — whether to approach or retreat, for instance — and to prompt the associated behaviors. Emerging evidence indicates that the lateral septum may be involved in this process (Menon et al., 2022). This brain area – which is mostly formed of inhibitory neurons that repress the activity of the cells they project onto – is known to help shape social and emotional behaviors. The lateral septum receives projections from both the dorsal and ventral segments of the hippocampus and, in turn, connects with various regions involved in goal-directed behaviors. This includes the ventral tegmental area (or VTA; Rizzi-Wise and Wang, 2021). When dopaminergic neurons in this part of the brain are activated, such as during novel social interactions, they help drive the exploration of new stimuli and conspecifics (Gunaydin et al., 2014; Solié et al., 2022; Molas et al., 2024). Yet many of these pathways remain poorly understood. In particular, it is still unclear how the ventral hippocampus interacts with the lateral septum and the VTA to ‘transform’ social memories into motivations that promote individuals to investigate new conspecifics.
Now, in eLife, Malavika Murugan and colleagues at Emory University – including Maha Rashid as first author – report a new pathway between the ventral hippocampus, the lateral septum, and the VTA that regulates social novelty preference in mice (Figure 1; Rashid et al., 2024). To identify this circuit, the team carried out a social discrimination test which involved placing a mouse in an open chamber alongside two conspecifics of the same age and sex, which were caged on opposite sides of the apparatus. Only one of these individuals was known to the test subject, as they had been housed together for 72hours prior to the experiment. This is a much longer period than used in other protocols, allowing the animals to better recognize the features of the familiar peer.
Figure 1
A neuronal circuit controlling social preferences.
vCA1 neurons (pink) in the ventral hippocampus encode social information and project to the lateral septum (LS; green), a region involved in social motivation. Lateral septum neurons establish monosynaptic connections onto dopaminergic neurons in the ventral tegmental area (VTA; blue), which promote exploration (green arrow) of new individuals.
© 2024, BioRender Inc. Figure 1 was created using BioRender, and is published under a CC BY-NC-ND license. Further reproductions must adhere to the terms of this license.
Preference for social novelty was determined by the amount of time the subject spent exploring the new individual relative to the familiar one. Without interventions, the mouse spent longer around the new conspecific.
Rashid et al. then used a technique known as chemogenetics to deactivate the neural pathway connecting the ventral hippocampus to the lateral septum, as this allowed them to assess whether these projections are required for animals to discriminate between novel and familiar social stimuli. The treatment did not affect the mice’s tendency to investigate new foods or objects more, but it disrupted their preference for social novelty (that is, the animals spent similar amounts of time investigating unknown and familiar individuals).
The team then used optogenetics to explore this effect in more detail, as this approach makes it possible to temporarily deactivate the pathway ‘at will’ as the animals perform the test. The experiments showed that the mice preferred investigating the conspecific that had been physically closest to them at the time their pathway had been silenced. Switching off the pathway promoted investigative behaviors towards a familiar individual (with the mice then having less time to spend exploring the unknown conspecific). In addition, if exposed to two new peers, the subjects explored the one which had been nearby during the manipulation. Overall, this suggests that preventing the activation of this pathway results in social investigations being more engaging. This led Rashid et al. to propose that the ventral hippocampus-lateral septum pathway may inhibit downstream regions which drive exploration of new social stimuli, such as the VTA.
The team therefore examined next whether the ventral hippocampus projects onto the pathway connecting the lateral septum to the VTA. To do so, they used monosynaptic rabies tracing, a method that helps reveal which neurons directly communicate with a specific cell. This allowed Rashid et al. to establish that the ventral hippocampus innervates cells in the lateral septum which connect to the VTA; disrupting the latter pathway with chemogenetic tools also prevented the preference for a novel mouse. Crucially, rabies tracing allowed Rashid et al. to show that neurons in the lateral septum directly project onto dopaminergic neurons in the VTA. In particular, the rostral part of the lateral septum, a subdivision recently implicated in the shift from novel to familiar social preferences in young mice, projected most strongly to the dopaminergic cells (de León Reyes et al., 2023).
Taken together, these results reveal a pathway connecting social memories stored in the ventral hippocampus to the centers responsible for motivational social behaviors (Figure 1). Ventral hippocampal cells connect to lateral septum neurons that are important for social behavior, which, in turn, project to VTA dopaminergic centers that control the animal’s social approach. Inhibition of the hippocampal-septal pathway disinhibits these VTA centers, resulting in the mouse being more interested in novel social interactions. These findings will aid in developing new therapies that improve social impairments in numerous neurodevelopmental and neuropsychiatric disorders.
References
-
Neurobiology of the lateral septum: regulation of social behaviorTrends in Neurosciences 45:27–40.https://doi.org/10.1016/j.tins.2021.10.010
-
Ventral CA1 neurons store social memoryScience 353:1536–1541.https://doi.org/10.1126/science.aaf7003
-
Midbrain circuits of novelty processingNeurobiology of Learning and Memory 176:107323.https://doi.org/10.1016/j.nlm.2020.107323
Article and author information
Author details
Publication history
Copyright
© 2024, Keppler and Molas
This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 546
- views
-
- 43
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Behavior: Prompting social investigation
eLife 13:e99363.
https://doi.org/10.7554/eLife.99363
Further reading
-
- Neuroscience
The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick’s 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick’s model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.
-
- Neuroscience
Complex macro-scale patterns of brain activity that emerge during periods of wakeful rest provide insight into the organisation of neural function, how these differentiate individuals based on their traits, and the neural basis of different types of self-generated thoughts. Although brain activity during wakeful rest is valuable for understanding important features of human cognition, its unconstrained nature makes it difficult to disentangle neural features related to personality traits from those related to the thoughts occurring at rest. Our study builds on recent perspectives from work on ongoing conscious thought that highlight the interactions between three brain networks – ventral and dorsal attention networks, as well as the default mode network. We combined measures of personality with state-of-the-art indices of ongoing thoughts at rest and brain imaging analysis and explored whether this ‘tri-partite’ view can provide a framework within which to understand the contribution of states and traits to observed patterns of neural activity at rest. To capture macro-scale relationships between different brain systems, we calculated cortical gradients to describe brain organisation in a low-dimensional space. Our analysis established that for more introverted individuals, regions of the ventral attention network were functionally more aligned to regions of the somatomotor system and the default mode network. At the same time, a pattern of detailed self-generated thought was associated with a decoupling of regions of dorsal attention from regions in the default mode network. Our study, therefore, establishes that interactions between attention systems and the default mode network are important influences on ongoing thought at rest and highlights the value of integrating contemporary perspectives on conscious experience when understanding patterns of brain activity at rest.
