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Optogenetic silencing of hippocampal inputs to the retrosplenial cortex causes a prolonged disruption of working memory performance


Core Concepts
Silencing hippocampal inputs to the retrosplenial cortex impairs working memory performance, with effects outlasting the period of optogenetic manipulation.
Abstract
The study investigates the role of direct synaptic connections between the hippocampus and retrosplenial cortex (RSC) in working memory (WM) performance. Using a delayed non-match to place (DNMP) task in rats, the authors optogenetically silenced hippocampal terminals in the RSC during the retrieval phase. Key findings: Silencing hippocampal inputs to RSC significantly decreased WM performance in eArch+ animals compared to controls, with effects seen in both illuminated and non-illuminated trials. The impairment outlasted the period of optogenetic silencing, affecting performance up to 3 subsequent trials. eArch+ animals exhibited increased errors even after incorrect trials, suggesting the silencing disrupted the ability to use action-outcome associations to correct behavior. Silencing hippocampal inputs to RSC caused animals to spend less time at the choice point, indicating hastier and more erroneous decision-making. The results demonstrate that direct hippocampal inputs to RSC are necessary for the proper functioning of WM, likely by conveying contextual and episodic information to guide goal-directed behavior. The prolonged effects of optogenetic silencing suggest that synaptic transmission, rather than just neuronal spiking, is a critical mechanism underlying this hippocampal-cortical coordination during WM.
Stats
Silencing hippocampal terminals in RSC significantly decreased working memory performance in eArch+ animals compared to controls (CTRL: 0.81±0.03, ARCH: 0.73±0.08, GLMM, p=0.006). In eArch+ animals, both illuminated (TI) and non-illuminated (NI) trials during the experiment had significantly lower performance compared to baseline and CTRL animals (TI, p=0.02; NI, p=0.008). The probability of a correct trial was lower in eArch+ animals when the previous 1-3 trials were illuminated (T-1, p=0.01; T-2, p=0.033; T-3, p=0.036). eArch+ animals exhibited increased errors even after incorrect trials, compared to CTRL (p<0.001), an effect absent during baseline sessions (p=0.172). CTRL animals spent more time at the choice point compared to eArch+ animals (p=0.02), specifically on correct trials (Correct NI, p=0.008; Correct TI, p=0.045).
Quotes
"Silencing HIPP terminals by delivering green light (525 nm) to RSC in eArch+ animals significantly decreased working memory performance." "Such decreased performance is seen in eArch+ animals, regardless of whether the one trial analyzed is illuminated." "eArch+ animals exhibit increased errors even following incorrect responses, contrary to what happens during baseline sessions where no light is ever delivered, and error rates are generally low for both eArch+ and CTRL animals."

Deeper Inquiries

How might the prolonged effects of optogenetic silencing on synaptic transmission relate to specific mechanisms of synaptic plasticity in the hippocampal-retrosplenial circuit?

The prolonged effects of optogenetic silencing on synaptic transmission in the hippocampal-retrosplenial circuit could be related to specific mechanisms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are processes that involve the strengthening or weakening of synaptic connections, respectively, and are crucial for learning and memory. When synaptic transmission is disrupted through optogenetic silencing, it can lead to alterations in the balance between LTP and LTD, affecting the overall plasticity of the circuit. This disruption may result in persistent changes in synaptic efficacy, impacting the ability of neurons to communicate effectively and encode new information.

What other cognitive functions, beyond working memory, might be impacted by disrupting the flow of contextual information from the hippocampus to the retrosplenial cortex?

Disrupting the flow of contextual information from the hippocampus to the retrosplenial cortex can impact a range of cognitive functions beyond working memory. One such function is spatial navigation and orientation, as the retrosplenial cortex plays a crucial role in processing spatial information and integrating it with memory. Disruption in this flow of information can lead to difficulties in spatial learning, navigation, and orientation. Additionally, disruptions in this circuit may affect episodic memory, as the hippocampus is essential for encoding and retrieving episodic memories, and the retrosplenial cortex is involved in contextual processing of these memories. Therefore, disruptions in this circuit may impair the ability to recall past events and experiences accurately.

Could the hastier decision-making observed in eArch+ animals during the working memory task be related to broader changes in decision-making strategies or goal-directed behavior?

The hastier decision-making observed in eArch+ animals during the working memory task could indeed be related to broader changes in decision-making strategies and goal-directed behavior. Optogenetic silencing of hippocampal inputs to the retrosplenial cortex may disrupt the integration of contextual information necessary for making accurate decisions based on past experiences. This disruption could lead to impulsive or hasty decision-making, as the animals may struggle to retrieve and utilize relevant information from memory to guide their choices. Additionally, alterations in this circuit may impact the ability to plan and execute goal-directed behaviors effectively, as the flow of information critical for goal-oriented actions is disrupted. Therefore, the observed hastier decision-making in eArch+ animals may reflect a broader impairment in decision-making strategies and goal-directed behavior resulting from the disruption of the hippocampal-retrosplenial circuit.
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